Pyridazinone

ABSTRACT

The invention relates to novel compounds, to a method for the production of said compounds and to the use thereof as medicaments, more particularly as antiviral agents, especially against cytomegalovirus.

The present invention relates to novel compounds, to processes for theirpreparation and to their use as medicaments, in particular as antiviralagents, in particular against cytomegaloviruses.

EP-A-071 102 describes benzotriazole-substituted pyridazinones forcardiovascular disorders. EP-A-839 1 describes benzimidazole-substitutedpyridazinones for cardiovascular disorders and with antiviral action.

The present invention relates to compounds of the general formula (I)

in which

-   -   A is attached via position 2, 3, 5 or 6 to the aromatic ring and    -   A represents oxygen or NR⁶,    -   E represents oxygen, CR⁹R¹⁰ or NR⁷,    -   Y represents oxygen or NR⁸,    -   D and X are identical or different and represent in each case        oxygen or sulfur,    -   G represents hydrogen,    -   or    -   G represents C₆-C₁₀-aryl, where C₆-C₁₀-aryl may optionally be        substituted by up to three substituents selected from the group        consisting of halogen, hydroxyl, nitro, cyano, C₁-C₆-alkoxy,        hydroxy-carbonyl, C₁-C₆-alkoxycarbonyl, amino, mono- or        di-C₁-C₆-alkylamino, mono- or di-C₁-C₆-alkylaminocarbonyl and        C₁-C₆-alkyl,        -   where        -   C₁-C₆-alkoxy, C₁-C₆-alkoxycarbonyl, mono- or            di-C₁-C₆-alkylamino, mono- or di-C₁-C₆-alkylaminocarbonyl or            C₁-C₆-alkyl may optionally be substituted by up to three            substituents selected from the group consisting of halogen,            hydroxyl, C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,            hydroxycarbonyl, C₁-C₆-alkoxycarbonyl, mono- or            C₁-C₆-alkylaminocarbonyl and C₆-C₁₀-aryl,    -   or    -   G represents C₆-C₁₀-aryl, where C₆-C₁₀-aryl may optionally be        substituted by phenyl,        -   where        -   phenyl may optionally be substituted by up to three            substituents selected from the group consisting of halogen,            hydroxyl, C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,            hydroxycarbonyl, C₁-C₆-alkoxycarbonyl, mono- or            di-C₁-C₆-alkylaminocarbonyl and C₁-C₆-alkyl,        -   where        -   C₁-C₆-alkyl for its part may optionally be substituted by up            to three substituents selected from the group consisting of            hydroxyl, C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,            hydroxycarbonyl, C₁-C₆-alkoxycarbonyl and mono- or            di-C₁-C₆-alkylaminocarbonyl,    -   or    -   G represents C₆-C₁₀-aryl, where C₆-C₁₀-aryl may optionally be        substituted by phenyl,        -   where        -   phenyl may optionally be substituted by C₅-C₆-heteroaryl or            C₅-C₇-heterocyclyl,        -   where        -   C₅-C₆-heteroaryl or C₅-C₇-heterocyclyl for their part may            optionally be substituted by up to three substituents            selected from the group consisting of halogen, C₁-C₆-alkyl,            C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,            hydroxycarbonyl, C₁-C₆-alkoxycarbonyl and mono- or            di-C₁-C₆-alkylaminocarbonyl,    -   or    -   G represents C₆-C₁₀-aryl, where C₆-C₁₀-aryl may optionally be        substituted by a group of the following formula    -   or    -   G represents C₅-C₁₀-heteroaryl or C₅-C₇-heterocyclyl, where        C₅-C₁₀-heteroaryl or C₅-C₇-heterocyclyl may optionally be        substituted by up to three substituents selected from the group        consisting of halogen, nitro, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy,        amino, mono- or di-C₁-C₆-alkylamino, hydroxycarbonyl,        C₁-C₆-alkoxycarbonyl and mono or di-C₁-C₆-alkylaminocarbonyl,    -   or    -   G represents C₃-C₁₀-cycloalkyl, where C₃-C₁₀-cycloalkyl may        optionally be substituted by up to three substituents selected        from the group consisting of halogen, nitro, cyano, hydroxyl,        C₁-C₆-alkyl, C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,        C₁-C₆-alkylcarbonylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl        and mono or di-C₁-C₆-alkylaminocarbonyl,    -   R¹, R², R³ and R⁴ are identical or different and each represent        hydrogen, amino, mono- or di-C₁-C₆-alkylamino,        C₁-C₆-alkylcarbonylamino, C₆-C₁₀-aryl or C₁-C₆-alkyl, where        C₁-C₆-alkyl may optionally be substituted by up to three        substituents selected from the group consisting of hydroxyl,        C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,        C₁-C₆-alkylcarbonylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl        and mono or di-C₁-C₆-alkylaminocarbonyl,        -   and        -   where C₆-C₁₀-aryl may optionally be substituted by up to            three substituents selected from the group consisting of            halogen, hydroxyl, C₁-C₆-alkoxy, amino, mono- or            di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino,            hydroxycarbonyl, C₁-C₆-alkoxycarbonyl, mono or            di-C₁-C₆-alkylaminocarbonyl and C₁-C₆-alkyl,        -   where        -   C₁-C₆-alkyl may optionally be substituted by up to three            substituents selected from the group consisting of hydroxyl,            C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,            C₁-C₆-alkylcarbonylamino, hydroxycarbonyl,            C₁-C₆-alkoxycarbonyl and mono- or            di-C₁-C₆-alkylaminocarbonyl,    -   or    -   R¹ and R² or R³ and R⁴ together with the carbon atom to which        they are attached form a C₃-C₆-cycloalkyl ring, where the        C₃-C₆-cycloalkyl ring may optionally be substituted by up to        three substituents selected from the group consisting of        halogen, hydroxyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, amino, mono- or        di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino, hydroxycarbonyl,        C₁-C₆-alkoxycarbonyl and mono- or di-C₁-C₆-alkylaminocarbonyl,    -   or    -   R¹ and R³ together with the carbon atoms to which they are        attached form a C₃-C₆-cycloalkyl ring, where the        C₃-C₆-cycloalkyl ring may optionally be substituted by up to        three substituents selected from the group consisting of        halogen, hydroxyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, amino, mono- or        di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino, hydroxycarbonyl,        C₁-C₆-alkoxycarbonyl and mono- or di-C₁-C₆-alkylaminocarbonyl,    -   R⁵ represents hydrogen, halogen, hydroxyl, C₁-C₆-alkoxy, amino,        mono- or di-C₁-C₆-alkylamino or C₁-C₆-alkyl, where C₁-C₆-alkoxy,        mono- or di-C₁-C₆-alkylamino or C₁-C₆-alkyl may optionally be        substituted by up to three substituents selected from the group        consisting of hydroxyl, C₁-C₆-alkoxy, amino, mono- or        di-C₁-C₆-alkylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl and        mono- or di-C₁-C₆-alkylaminocarbonyl,    -   R⁶, R⁷ and R⁸ are identical or different and represent in each        case hydrogen or C₁-C₆-alkyl, where C₁-C₆-alkyl may optionally        be substituted by up to three substituents selected from the        group consisting of hydroxyl, C₁-C₆-alkoxy, amino, mono- or        di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino, hydroxycarbonyl,        C₁-C₆-alkoxycarbonyl and mono- or di-C₁-C₆-alkylaminocarbonyl,    -   R⁹ and R¹⁰ are identical or different and represent in each case        hydrogen, NR¹¹R¹², OR¹³ or C₁-C₆-alkyl, where C₁-C₆-alkyl may        optionally be substituted by up to three substituents selected        from the group consisting of hydroxyl, C₁-C₆-alkoxy, amino,        mono- or di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino,        hydroxycarbonyl, C₁-C₆-alkoxycarbonyl and mono- or        di-C₁-C₆-alkylaminocarbonyl,    -   R¹¹, R¹² and R¹³ are identical or different and represent in        each case hydrogen or C₁-C₆-alkyl, where C₁-C₆-alkyl may        optionally be substituted by up to three substituents selected        from the group consisting of hydroxyl, C₁-C₆-alkoxy, amino,        mono- or di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino,        hydroxycarbonyl, C₁-C₆-alkoxycarbonyl and mono- or        di-C₁-C₆-alkylaminocarbonyl,        and their tautomers, stereioisomers, stereoisomeric mixtures and        their pharmacologically acceptable salts.

In the context of the invention, C₁-C₃-alkyl, C₁-C₄-alkyl, C₁-C₆-alkylrepresent a straight-chain or branched alkyl radical having 1 to 3, 1 to4 and 1 to 6 carbon atoms, respectively. Examples which may be mentionedare: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,n-pentyl and n-hexyl.

In the context of the invention, C₃-C₆-cycloalkyl, C₃-C₁₀-cycloalkylrepresent a cycloalkyl group having 3 to 6 and 3 to 10 carbon atoms,respectively. Examples which may be mentioned are: cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.

In the context of the invention, C₁-C₆-alkoxy represents astraight-chain, branched or cyclic alkyl radical having 1 to 6 carbonatoms which is attached via an oxygen atom. Examples which may bementioned are: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy,n-pentoxy and n-hexoxy. Unless indicated otherwise, preference is givento straight-chain or branched alkyl radicals having 1 to 6 carbon atoms,for example methoxy and ethoxy.

In the context of the invention, C₁-C₆-alkoxycarbonyl represents astraight-chain, branched or cyclic alkoxy radical having 1 to 6 carbonatoms which is attached via a carbonyl group. Examples which may bementioned are: methoxycarbonyl, ethoxy-carbonyl, n-propoxycarbonyl,isopropoxycarbonyl and tert-butoxycarbonyl. Unless indicated otherwise,preference is given to straight-chain or branched alkoxy radicals having1 to 6 carbon atoms.

In the context of the invention, C₆-C₁₀-aryl represents an aromaticradical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyland naphthyl.

In the context of the invention, mono-C₁-C₆-alkylamino represents anamino group having a straight-chain, branched or cyclic alkylsubstituent which has 1 to 6 carbon atoms. Examples which may bementioned are: methylamino, ethylamino, n-propylamino, isopropylamino,cyclopropylamino, t-butylamino, n-pentylamino, cyclopentylamino andn-hexylamino.

In the context of the invention, di-C₁-C₆-alkylamino represents an aminogroup having two identical or different straight-chain, branched orcyclic alkyl substituents, each of which has 1 to 6 carbon atoms.Examples which may be mentioned are: N,N-dimethylamino,N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-methyl-N-cyclopropylamino, N-isopropyl-N-n-propylamino,N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino andN-n-hexyl-N-methylamino.

In the context of the invention, mono-C₁-C₆-alkylaminocarbonylrepresents an amino group having a straight-chain, branched or cyclicalkyl substituent which has 1 to 6 carbon atoms and which is attachedvia a carbonyl group. Examples which may be mentioned are:methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl,isopropylaminocarbonyl, cyclopropylaminocarbonyl, t-butylaminocarbonyl,n-pentylaminocarbonyl, cyclopentylaminocarbonyl andn-hexylaminocarbonyl.

In the context of the invention, di-C₁-C₆-alkylaminocarbonyl representsan amino group having two identical or different straight-chain,branched or cyclic alkyl substituents, each of which has 1 to 6 carbonatoms, and which is attached via a carbonyl group. Examples which may bementioned are: N,N-dimethyl-aminocarbonyl, N,N-diethylaminocarbonyl,N-ethyl-N-methylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl,N-methyl-N-cyclopropylaminocarbonyl,N-isopropyl-N-n-propylaminocarbonyl, N-t-butyl-N-methylaminocarbonyl,N-ethyl-N-n-pentylaminocarbonyl and N-n-hexyl-N-methylaminocarbonyl.

In the context of the invention, halogen generally represents fluorine,chlorine, bromine and iodine. Preference is given to fluorine, chlorineand bromine. Particular preference is given to fluorine and chlorine.

In the context of the invention, 5- to 10-membered heteroaryl(“C₅-C₁₀-heteroaryl”) represents 5- to 10-membered aromatic rings whichcomprise heteroatoms and have at least one aromatic ring and which maycomprise 1 to 4 heteroatoms selected from the group consisting of O, Sand N. Heteroaryl for its part may also be substituted via C or N.Examples which may be mentioned are: pyridyl, furyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolicenyl,indolyl, benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolyl,isoquinolyl, naphthyridinyl, quinazolinyl, etc.

In the context of the invention, a 5- to 7-membered saturated orpartially unsaturated heterocycle (“C₅-C₇-heterocyclyl”) having up to 3heteroatoms from the group consisting of S, N and O generally representsa heterocycle which may contain one or more double bonds and which isattached via a ring carbon atom or a ring nitrogen atom. Heterocyclylfor its part may also be substituted via C or N. Examples which may bementioned are: tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl,dihydropyridinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl.Preference is given to piperidinyl, morpholinyl and pyrrolidinyl.

In the context of the invention, preferred salts are physiologicallyacceptable salts of the compounds according to the invention.

Physiologically acceptable salts of the compounds according to theinvention can be acid addition salts of the substances according to theinvention with mineral acids, carboxylic acids or sulfonic acids.Particular preference is, for example, given to salts with hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonicacid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid,naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid,tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

However, salts that may also be mentioned include salts with customarybases such as, for example, alkali metal salts (for example sodium orpotassium salts), alkaline earth metal salts (for example calcium ormagnesium salts) or ammonium salts derived from ammonia or organicamines, such as, for example, diethylamine, triethylamine,ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine,dihydroabietylamine, 1-ephenamine or methylpiperidine, or derived fromnatural amino acids, such as, for example, glycine, lysine, arginine orhistidine.

The compounds according to the invention can exist in stereoisomericforms which are either like image and mirror image (enantiomers) orwhich are not like image and mirror image (diastereomers). The inventionrelates both to the enantiomers or diastereomers or to their respectivemixtures. The racemates, like the diastereomers, can be separated in aknown manner into the stereoisomerically uniform components.

The compounds according to the invention can also be present asprodrugs. This applies in particular to the hydroxyl group on R⁵ whichcan be esterified without any substantial loss in activity. Theseinclude, by way of example and by way of preference, aliphatic esters,for example butyl esters, aromatic esters, for example benzyl esters, orα-amino acid esters, for example succinic acid monoamide.

Preference is given to compounds of the general formula (I) in which

-   -   A is attached via position 2, 3, 5 or 6 to the aromatic ring,        and    -   A represents oxygen or NR⁶,    -   E represents oxygen, CR⁹R¹⁰ or NR⁷,    -   Y represents oxygen or NR⁸,    -   D and X are identical or different and represent in each case        oxygen or sulfur,    -   G represents hydrogen,    -   or    -   G represents C₆-C₁₀-aryl, where C₆-C₁₀-aryl may optionally be        substituted by up to three substituents independently of one        another selected from the group consisting of halogen, hydroxyl,        nitro, cyano, C₁-C₆-alkoxy, hydroxycarbonyl,        C₁-C₆-alkoxycarbonyl, amino, mono- or di-C₁-C₆-alkylamino, mono-        or di-C₁-C₆-alkylaminocarbonyl and C₁-C₆-alkyl,        -   where        -   C₁-C₆-alkoxy, C₁-C₆-alkoxycarbonyl, mono- or            di-C₁-C₆-alkylamino, mono- or di-C₁-C₆-alkylaminocarbonyl or            C₁-C₆-alkyl may optionally be substituted by up to three            substituents independently of one another selected from the            group consisting of halogen, hydroxyl, C₁-C₆-alkoxy, amino,            mono- or di-C₁-C₆-alkylamino, hydroxycarbonyl,            C₁-C₆-alkoxycarbonyl, mono- or di-C₁-C₆-alkylaminocarbonyl            and C₆-C₁₀-aryl,    -   or    -   G represents C₆-C₁₀-aryl, where C₆-C₁₀-aryl may optionally be        substituted by phenyl,        -   where        -   phenyl may optionally be substituted by up to three            substituents independently of one another selected from the            group consisting of halogen, hydroxyl, C₁-C₆-alkoxy, amino,            mono- or di-C₁-C₆-alkylamino, hydroxycarbonyl,            C₁-C₆-alkoxycarbonyl, mono- or di-C₁-C₆-alkylaminocarbonyl            and C₁-C₆-alkyl,        -   where        -   C₁-C₆-alkyl for its part may optionally be substituted by up            to three substituents independently of one another selected            from the group consisting of hydroxyl, C₁-C₆-alkoxy, amino,            mono- or di-C₁-C₆-alkylamino, hydroxycarbonyl,            C₁-C₆-alkoxycarbonyl and mono- or            di-C₁-C₆-alkylaminocarbonyl,    -   or    -   G represents C₆-C₁₀-aryl, where C₆-C₁₀-aryl may optionally be        substituted by phenyl,        -   where        -   phenyl may optionally be substituted by C₅-C₆-heteroaryl or            C₅-C₇-heterocyclyl,        -   where        -   C₅-C₆-heteroaryl or C₅-C₇-heterocyclyl for their part may            optionally be substituted by up to three substituents            independently of one another selected from the group            consisting of halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, amino,            mono- or di-C₁-C₆-alkylamino, hydroxycarbonyl,            C₁-C₆-alkoxycarbonyl and mono- or            di-C₁-C₆-alkylaminocarbonyl,    -   or    -   G represents C₆-C₁₀-aryl, where C₆-C₁₀-aryl may optionally be        substituted by a group of the following formula    -   or    -   G represents C₅-C₁₀-heteroaryl or C₅-C₇-heterocyclyl, where        C₅-C₁₀-heteroaryl or C₅-C₇-heterocyclyl may optionally be        substituted by up to three substituents independently of one        another selected from the group consisting of halogen, nitro,        cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy, amino, mono- or        di-C₁-C₆-alkylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl and        mono- or di-C₁-C₆-alkylaminocarbonyl,    -   or    -   G represents C₃-C₁₀-cycloalkyl, where C₃-C₁₀-cycloalkyl may        optionally be substituted by up to three substituents        independently of one another selected from the group consisting        of halogen, nitro, cyano, hydroxyl, C₁-C₆-alkyl, C₁-C₆-alkoxy,        amino, mono- or di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino,        hydroxycarbonyl, C₁-C₆-alkoxycarbonyl and mono- or        di-C₁-C₆-alkylaminocarbonyl,    -   R¹, R², R³ and R⁴ are identical or different and represent in        each case hydrogen, amino, mono- or di-C₁-C₆-alkylamino,        C₁-C₆-alkylcarbonylamino, C₆-C₁₀-aryl or C₁-C₆-alkyl, where        C₁-C₆-alkyl may optionally be substituted by up to three        substituents independently of one another selected from the        group consisting of hydroxyl, C₁-C₆-alkoxy, amino, mono- or        di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino, hydroxycarbonyl,        C₁-C₆-alkoxycarbonyl and mono- or di-C₁-C₆-alkylaminocarbonyl,        -   and        -   where C₆-C₁₀-aryl may optionally be substituted by up to            three substituents selected from the group consisting of            halogen, hydroxyl, C₁-C₆-alkoxy, amino, mono- or            di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino,            hydroxycarbonyl, C₁-C₆-alkoxycarbonyl, mono- or            di-C₁-C₆-alkylaminocarbonyl and C₁-C₆-alkyl,        -   where        -   C₁-C₆-alkyl may optionally be substituted by up to three            substituents independently of one another selected from the            group consisting of hydroxyl, C₁-C₆-alkoxy, amino, mono- or            di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino,            hydroxycarbonyl, C₁-C₆-alkoxycarbonyl and mono- or            di-C₁-C₆-alkylaminocarbonyl,    -   where R¹, R², R³ and R⁴ are not simultaneously hydrogen,    -   or    -   R¹ and R² or R³ and R⁴ together with the carbon atom to which        they are attached form a C₃-C₆-cycloalkyl ring, where the        C₃-C₆-cycloalkyl ring may optionally be substituted by up to        three substituents independently of one another selected from        the group consisting of halogen, hydroxyl, C₁-C₆-alkyl,        C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,        C₁-C₆-alkylcarbonylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl        and mono- or di-C₁-C₆-alkylaminocarbonyl,    -   or    -   R¹ and R³ together with the carbon atoms to which they are        attached form a C₃-C₆-cycloalkyl ring, where the        C₃-C₆-cycloalkyl ring may optionally be substituted by up to        three substituents independently of one another selected from        the group consisting of halogen, hydroxyl, C₁-C₆-alkyl,        C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,        C₁-C₆-alkylcarbonylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl        and mono- or di-C₁-C₆-alkylaminocarbonyl,    -   R⁵ represents hydrogen, halogen, hydroxyl, C₁-C₆-alkoxy, amino,        mono- or di-C₁-C₆-alkylamino or C₁-C₆-alkyl, where C₁-C₆-alkoxy,        mono- or di-C₁-C₆-alkylamino or C₁-C₆-alkyl may optionally be        substituted by up to three substituents independently of one        another selected from the group consisting of hydroxyl,        C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,        hydroxycarbonyl, C₁-C₆-alkoxycarbonyl and mono- or        di-C₁-C₆-alkylaminocarbonyl,    -   R⁶, R⁷ and R⁸ are identical or different and represent in each        case hydrogen or C₁-C₆-alkyl, where C₁-C₆-alkyl may optionally        be substituted by up to three substituents independently of one        another selected from the group consisting of hydroxyl,        C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,        C₁-C₆-alkylcarbonylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl        and mono- or di-C₁-C₆-alkylaminocarbonyl,    -   R⁹ and R¹⁰ are identical or different and represent in each case        hydrogen, NR¹¹R¹², OR¹³ or C₁-C₆-alkyl, where C₁-C₆-alkyl may        optionally be substituted by up to three substituents        independently of one another selected from the group consisting        of hydroxyl, C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,        C₁-C₆-alkylcarbonylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl        and mono- or di-C₁-C₆-alkylaminocarbonyl,    -   R¹¹, R¹² and R¹³ are identical or different and represent in        each case hydrogen or C₁-C₆-alkyl, where C₁-C₆-alkyl may        optionally be substituted by up to three substituents selected        from the group consisting of hydroxyl, C₁-C₆-alkoxy, amino,        mono- or di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino,        hydroxycarbonyl, C₁-C₆-alkoxycarbonyl and mono- or        di-C₁-C₆-alkylaminocarbonyl,    -   and their tautomers, stereoisomers, stereoisomeric mixtures and        their pharmacologically acceptable salts.

Preference is also given to compounds of the general formula (I) inwhich

-   -   A is attached via position 2, 3, 5 or 6 to the aromatic ring and    -   A represents NR⁶,    -   E represents NR⁷,    -   Y represents NR⁸,    -   D and X represent oxygen,    -   G represents C₆-C₁₀-aryl, where C₆-C₁₀-aryl may optionally be        substituted by up to three substituents independently of one        another selected from the group consisting of halogen, hydroxyl,        cyano and C₁-C₆-alkyl,        -   where        -   C₁-C₆-alkyl may optionally be substituted by up to three            substituents of halogen,    -   or    -   G represents C₅-C₆-heteroaryl, where C₅-C₆-heteroaryl may        optionally be substituted by up to three substituents        independently of one another selected from the group consisting        of halogen and C₁-C₃-alkyl,    -   or    -   G represents C₃-C₁₀-cycloalkyl, where C₃-C₁₀-cycloalkyl may        optionally be substituted by up to three substituents        C₁-C₆-alkyl,    -   R¹, R² and R³ are identical or different and represent in each        case hydrogen or represent C₁-C₃-alkyl,    -   R⁴ represents hydrogen, C₆-C₁₀-aryl or C₁-C₆-alkyl, where        C₁-C₆-alkyl may optionally be substituted by up to three        substituents independently of one another selected from the        group consisting of hydroxyl, C₁-C₆-alkoxy, amino, mono- or        di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino, hydroxycarbonyl,        C₁-C₆-alkoxycarbonyl and mono- or di-C₁-C₆-alkylaminocarbonyl,        -   and        -   where C₆-C₁₀-aryl may optionally be substituted by up to            three substituents independently of one another selected            from the group consisting of halogen, hydroxyl, C₁-C₆-alkoxy            and C₁-C₆-alkyl,    -   where R¹, R², R³ and R⁴ do not simultaneously represent        hydrogen,    -   R⁵ represents hydrogen, halogen, hydroxyl, amino, mono- or        di-C₁-C₆-alkylamino or C₁-C₆-alkyl, where C₁-C₆-alkyl may        optionally be substituted by up to three substituents        independently of one another selected from the group consisting        of hydroxyl, C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,        hydroxycarbonyl, C₁-C₆-alkoxycarbonyl and mono- or        di-C₁-C₆-alkylaminocarbonyl,    -   R⁶, R⁷ and R⁸ represent hydrogen,    -   and their tautomers, stereoisomers, stereoisomeric mixtures and        their pharmacologically acceptable salts.

Preference is given to compounds of the general formula (I)

in which

-   -   A is attached via position 2, 3, 5 or 6 to the aromatic ring and    -   A represents NR⁶,    -   E represents NR⁷,    -   Y represents NR⁸,    -   D and X represent oxygen,    -   G represents C₆-C₁₀-aryl, where C₆-C₁₀-aryl may optionally be        substituted by up to three substituents selected from the group        consisting of halogen or C₁-C₆-alkyl,        -   where        -   C₁-C₆-alkyl may optionally be substituted by up to three            substituents of halogen, preferably fluorine,    -   R¹, R², R³ and R⁴ are identical or different and each represent        hydrogen or represent C₁-C₃-alkyl,    -   R⁵ represents hydrogen,    -   R⁶, R⁷ and R⁸ represent hydrogen,    -   and their tautomers, stereoisomers, stereoisomeric mixtures and        their pharmacologically acceptable salts.

Preference is also given to compounds of the general formula (I) inwhich

-   -   A is attached via position 2, 3, 5 or 6 to the aromatic ring and    -   A represents NR⁶,    -   E represents NR⁷,    -   Y represents NR⁸,    -   D and X represent oxygen,    -   G represents C₆-C₁₀-aryl, where C₆-C₁₀-aryl may optionally be        substituted by up to three substituents selected from the group        consisting of halogen or C₁-C₆-alkyl,        -   where        -   C₁-C₆-alkyl may optionally be substituted by up to three            substituents of halogen, preferably fluorine,    -   R¹, R², R³ and R⁴ are identical or different and each represent        hydrogen or represent C₁-C₃-alkyl,    -   where R¹, R², R³ and R⁴ are not simultaneously hydrogen,    -   R⁵ represents hydrogen,    -   R⁶, R⁷ and R⁸ represent hydrogen,    -   and their tautomers, stereoisomers, stereoisomeric mixtures and        their pharmacologically acceptable salts.

In a further preferred embodiment, in the compounds of the generalformula (I) the radical A is attached via position 3 to the aromaticrings.

In a further preferred embodiment, D and X in the compounds of thegeneral formula (I) are oxygen.

In a further preferred embodiment, A, E and Y in the compounds of thegeneral formula (I) are NH.

In a further preferred embodiment, G in the compounds of the generalformula (I) is substituted phenyl.

In a further preferred embodiment, R¹, R² and R⁵ in the compounds of thegeneral formula (I) are hydrogen, and R³ and R⁴ are methyl.

In a further preferred embodiment, R⁵ in the compounds of the generalformula (I) is hydrogen, hydroxyl, chlorine or fluorine.

The invention furthermore relates to processes for preparing thecompounds of the formula (I).

In process

-   -   [A] compounds of the general formula (II)        in which    -   A is attached via position 2, 3, 5 or 6 to the aromatic ring and    -   R¹, R², R³, R⁴, R⁵, A, X and Y are as defined above    -   are reacted with compounds of the general formula (III)        D=C═N-G   (III)    -   in which    -   D and G are as defined above    -   to give compounds of the general formula (Ia)    -   in which    -   A is attached via position 2, 3, 5 or 6 to the aromatic ring and    -   R¹, R², R³, R⁴, R⁵, A, D, G, X and Y are as defined above,    -   in inert solvents which include halogenated hydrocarbons, such        as methylene chloride, trichloromethane, carbon tetrachloride,        trichloroethane, tetrachloroethane, 1,2-dichloroethane or        trichloroethylene, ethers, such as diethyl ether, methyl        tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran,        glycol dimethyl ether or diethylene glycol dimethyl ether,        hyrocarbons, such as benzene, xylene, toluene, hexane,        cyclohexane or mineral oil fractions, or other solvents, such as        ethyl acetate, acetone, dimethylformamide, dimethylacetamide,        2-butanone, dimethyl sulfoxide, acetonitrile or pyridine,        preferred solvents being tetrahydrofuran or methylene chloride,        if appropriate in the presence of a base, such as, for example,        alkali metal carbonates, such as cesium carbonate, sodium        carbonate or potassium carbonate, or potassium tert-butoxide, or        other bases, such as sodium hydride, DBU, triethylamine or        diisopropylethylamine, preferably triethylamine, preferably in a        temperature range of from room temperature to the reflux        temperature of the solvents, at atmospheric pressure.

Below, the compounds of the general formula (II) are represented as(IIa), (IIb) and (IIc).

The compounds of the general formula (III) are known or can besynthesized by known processes from the corresponding startingmaterials.

In Process

-   -   [B] compounds of the general formula (II) are reacted with        compounds of the general formula (IV)        in which    -   D, E and G are as defined above and    -   L¹ represents p-nitrophenyl or halogen, preferably bromine or        chlorine,    -   to give compounds of the general formula (I)    -   in which    -   A is attached via position 2, 3, 5 or 6 to the aromatic ring and    -   R¹, R², R³, R⁴, R⁵, A, D, E, G, X and Y are as defined above,    -   in inert solvents which include halogenated hydrocarbons, such        as methylene chloride, trichloromethane, carbon tetrachloride,        trichloroethane, tetrachloroethane, 1,2-dichloroethane or        trichloroethylene, ethers, such as diethyl ether, methyl        tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran,        glycol dimethyl ether or diethylene glycol dimethyl ether,        hyrocarbons, such as benzene, xylene, toluene, hexane,        cyclohexane or mineral oil fractions, or other solvents, such as        ethyl acetate, acetone, dimethylformamide, dimethylacetamide,        2-butanone, acetonitrile or pyridine, preferred solvents being        tetrahydrofuran or methylene chloride, if appropriate in the        presence of a base, such as, for example, alkali metal        carbonates, such as cesium carbonate, sodium carbonate or        potassium carbonate, or potassium tert-butoxide, or other bases,        such as sodium hydride, DBU, triethylamine or        diisopropylethylamine, preferably triethylamine, preferably in a        temperature range of from room temperature to the reflux        temperature of the solvents, at atmospheric pressure.

The compounds of the general formula (IV) are known or can be preparedby known processes from the corresponding starting materials

In process

-   -   [C] compounds of the general formula (V)        in which    -   —NCD is attached via position 2, 3, 5 or 6 to the aromatic ring        and    -   R¹, R², R³, R⁴, R⁵, D, X and Y are as defined above    -   are reacted with compounds of the general formula (VI)        H-M-G   (VI)    -   in which    -   G is as defined above and    -   M represents oxygen or NR⁷,        -   where        -   R⁷ is as defined above,    -   to give compounds of the general formula (Ib)    -   in which    -   —NH—C(D)-M-G is attached via position 2, 3, 5 or 6 to the        aromatic ring and    -   R¹, R², R³, R⁴, R⁵, D, G, M, X and Y are as defined above,    -   in inert solvents which include halogenated hydrocarbons, such        as methylene chloride, trichloromethane, carbon tetrachloride,        trichloroethane, tetrachloroethane, 1,2-dichloroethane or        trichloroethylene, ethers, such as diethyl ether, methyl        tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran,        glycol dimethyl ether or diethylene glycol dimethyl ether,        hyrocarbons, such as benzene, xylene, toluene, hexane,        cyclohexane or mineral oil fractions, or other solvents, such as        ethyl acetate, acetone, dimethylformamide, dimethylacetamide,        2-butanone, dimethyl sulfoxide, acetonitrile or pyridine,        preferred solvents being tetrahydrofuran or methylene chloride,        if appropriate in the presence of a base, such as, for example,        alkali metal carbonates, such as cesium carbonate, sodium        carbonate or potassium carbonate, or potassium tert-butoxide, or        other bases, such as sodium hydride, DBU, triethylamine or        diisopropylethylamine, preferably triethylamine, preferably in a        temperature range of from room temperature to the reflux        temperature of the solvents, at atmospheric pressure.

The compounds of the general formula (VI) are known or can besynthesized by known processes from the corresponding startingmaterials.

To prepare the compounds of the general formula (IIa)

in which

-   -   NH₂ is attached via position 2, 3, 5 or 6 to the aromatic ring        and    -   R¹, R², R³, R⁴, R⁵, X and Y are as defined above,    -   compounds of the general formula (VII)    -   in which    -   NO₂ is attached via position 2, 3, 5 or 6 to the aromatic ring        and    -   R¹, R², R³, R⁴ and R⁵ are as defined above    -   are, if X represents oxygen,    -   initially reacted with hydrazine, hydroxylamine or a compound of        the general formula (VIII)    -   in which    -   R⁸ is as defined above,    -   and the nitro group is then reduced to the amino group. These        two reactions can take place in one or two reaction steps.

In a one-step process, the reaction is carried out simultaneously withhydrazine and with palladium on carbon in inert solvents includingethers, such as diethyl ether, methyl tert-butyl ether,1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether ordiethylene glycol dimethyl ether, alcohols, such as methanol,n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons, suchas benzene, xylene, toluene, hexane, cyclohexane or mineral oilfractions, or other solvents, such as dimethylacetamide, acetonitrile orpyridine, preferred solvents being ethanol or isopropanol, preferably ina temperature range of from room temperature to the reflux temperatureof the solvents, at atmospheric pressure.

In a two-step process, the reaction is initially carried out usinghydrazine, hydroxylamine or a compound of the general formula (VIII) ininert solvents including ethers, such as diethyl ether, methyltert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycoldimethyl ether or diethylene glycol dimethyl ether, alcohols, such asmethanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol,hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane ormineral oil fractions, or other solvents, such as dimethylformamide,dimethylacetamide, acetonitrile or pyridine, preferred solvents beingethanol or isopropanol, preferably in a temperature range of from roomtemperature to the reflux temperature of the solvents, at atmosphericpressure.

In the second step, the reaction is carried out with hydrogen donors,preferably hydrazine or hydrogen and with palladium on carbon, or withtin chloride in inert solvents including ethers, such as diethyl ether,methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols,such as methanol, ethanol, n-propanol, isopropanol, n-butanol ortert-butanol, hydrocarbons, such as benzene, xylene, toluene, hexane,cyclohexane or mineral oil fractions, or other solvents, such as ethylacetate, dimethylformamide, dimethylacetamide, acetonitrile or pyridine,preferred solvents being ethanol, isopropanol or, in the case of tindichloride, in dimethylformamide, preferably in a temperature range offrom room temperature to the reflux temperature of the solvents, at fromatmospheric pressure to 3 bar.

If X is sulfur

-   -   the compound is initially reacted with hydrazine, hydroxylamine        or a compound of the general formula (VIII), the oxygen is then        changed for sulfur using Lawesson's reagent and the nitro group        is subsequently reduced to an amino group.

In the first step, the reaction is carried out with hydrazine,hydroxylamine or a compound of the general formula (VIII) in inertsolvents including ethers, such as diethyl ether, methyl tert-butylether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethylether or diethylene glycol dimethyl ether, alcohols, such as methanol,ethanol, n-propanol, isopropanol, n-butanol or tert-butanol,hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane ormineral oil fractions, or other solvents, such as dimethylformamide,dimethylacetamide, acetonitrile or pyridine, preferred solvents beingethanol or isopropanol, preferably in a temperature range of from roomtemperature to the reflux temperature of the solvents, at atmosphericpressure.

In the second step, the reaction is carried out with Lawesson's reagentin inert solvents including halogenated hydrocarbons, such as methylenechloride, trichloromethane, carbon tetrachloride, trichloroethane,tetrachloroethane, 1,2-dichloroethane or trichloroethylene, ethers, suchas diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons,such as benzene, xylene, toluene, hexane, cyclohexane or mineral oilfractions, or other solvents, such as nitromethane, 1,2-dimethoxyethane,dimethyl sulfoxide or pyridine, preferably toluene, xylene or dioxane,preferably in a temperature range of from room temperature to the refluxtemperature of the solvents, at atmospheric pressure.

In the third step, the reaction is carried out with hydrogen donors,preferably hydrazine or hydrogen and with palladium on carbon, or withtin dichloride in inert solvents including ethers, such as diethylether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane,tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethylether, alcohols, such as methanol, ethanol, n-propanol, isopropanol,n-butanol or tert-butanol, hydrocarbons, such as benzene, xylene,toluene, hexane, cyclohexane or mineral oil fractions, or othersolvents, such as dimethylformamide, dimethylacetamide, acetonitrile,pyridine, preferred solvents being ethanol, isopropanol or, in the caseof tin dichloride, in dimethylformamide, preferably in a temperaturerange of from room temperature to the reflux temperature of thesolvents, at from atmospheric pressure to 3 bar.

Compounds of the general formula (VII) can be present in two differentforms. In the description of the processes, only the open-chain form isshown.

To prepare the compounds of the general formula (IIb)

in which

-   -   NHR⁶ is attached via position 2, 3, 5 or 6 to the aromatic ring        and    -   R¹, R², R³, R⁴, R⁵, R⁶, X and Y are as defined above,    -   compounds of the general formula (IIa) are reacted with        compounds of the general formula (IX)        L²-R⁶   (IX)    -   in which    -   R⁶ is as defined above and    -   L² represents halogen, preferably bromine or iodine,    -   in inert solvents including ethers, such as diethyl ether,        methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane,        tetrahydrofuran, glycol dimethyl ether or diethylene glycol        dimethyl ether, hydrocarbons, such as benzene, xylene, toluene,        hexane, cyclohexane or mineral oil fractions, or other solvents,        such as dimethylformamide, dimethylacetamide, acetonitrile or        pyridine, preferred solvents being tetrahydrofuran or diethyl        ether, if appropriate in the presence of a base, such as, for        example, alkali metal hydroxides, such as sodium hydroxide or        potassium hydroxide, or alkali metal carbonates, such as cesium        carbonate, sodium carbonate or potassium carbonate, or amides,        such as sodium amide, lithium bis(trimethylsilyl)amide, lithium        diisopropylamide, or organometallic compounds, such as        butyllithium or phenyllithium, or other bases, such as sodium        hydride, DBU, triethylamine or diisopropylethylamine, preferably        diisopropylethylamine, potassium tert-butoxide or DBU,        preferably in a temperature range of from room temperature to        the reflux temperature of the solvents, at atmospheric pressure.

The compounds of the general formula (IX) are known or can besynthesized from the corresponding starting materials by knownprocesses.

To prepare compounds of the general formula (IIc)

in which

-   -   OH is attached via position 2, 3, 5 or 6 to the aromatic ring        and    -   R¹, R², R³, R⁴, R⁵, X and Y are as defined above,    -   initially the diazonium compounds are prepared from compounds of        the general formula (IIa) according to methods known to the        person skilled in the art, and these diazonium compounds are        then heated to give the phenols (cf. Organikum, 17th edition,        VEB Deutscher Verlag der Wissenschaften, Berlin, p. 543).

To prepare compounds of the general formula (V), compounds of thegeneral formula (IIa)

-   -   are reacted with trichloromethyl chloroformate    -   in inert solvents including halogenated hydrocarbons, such as        methylene chloride, trichloromethane, carbon tetrachloride,        trichloroethane, tetrachloroethane, 1,2-dichloroethane or        trichloroethylene, ethers, such as diethyl ether, methyl        tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran,        glycol dimethyl ether or diethylene glycol dimethyl ether,        hydrocarbons, such as benzene, xylene, toluene, hexane,        cyclohexane or mineral oil fractions, or other solvents, such as        ethyl acetate, acetone, dimethylformamide, dimethylacetamide,        2-butanone, acetonitrile or pyridine. Preferred solvents are        tetrahydrofuran or dichloromethane, if appropriate in the        presence of a base, such as, for example,        1,8-bis(dimethylamino)naphthalene, DBU, triethylamine or        diisopropylethylamine, preferably        1,8-bis(dimethylamino)-naphthalene, preferably in a temperature        range of from room temperature to the reflux temperature of the        solvents, at atmospheric pressure.

To prepare compounds of the general formula (VII), compounds of thegeneral formula (X)

in which

-   -   R¹, R², R³, R⁴ and R⁵ are as defined above    -   are reacted with fuming nitric acid, concentrated nitric acid or        nitrating acid, preferably in a temperature range of from        −30° C. to 0° C. at atmospheric pressure.

Compounds of the general formula (X) can be present in two differentforms. In the description of the processes, only the open-chain form isshown.

To prepare the compounds of the general formula (X), compounds of thegeneral formula (XI)

in which

-   -   R¹, R², R³ and R⁴ are as defined above    -   are reacted with compounds of the general formula (XII)    -   in which    -   R⁵ is as defined above    -   with Lewis acids, preferably aluminum trichloride,    -   in inert solvents including halogenated hydrocarbons, such as        methylene chloride, trichloromethane, carbon tetrachloride,        trichloroethane, tetrachloroethane, 1,2-dichloroethane or        trichloroethylene, ethers, such as diethyl ether, methyl        tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran,        glycol dimethyl ether or diethylene glycol dimethyl ether,        hydrocarbons, such as benzene, nitrobenzene, hexane, cyclohexane        or mineral oil fractions, or other solvents, such as ethyl        acetate, acetone, dimethylformamide, dimethylacetamide,        2-butanone, dimethyl sulfoxide, acetonitrile or pyridine (the        preferred solvent being 1,2-dichloroethane), preferably in a        temperature range of from −20° C. to room temperature at        atmospheric pressure.

The compounds of the general formulae (XI) and (XII) are known or can besynthesized from the corresponding starting materials by knownprocesses.

In an alternative synthesis route, to prepare the compounds of thegeneral formula (Xa), these compounds being compounds of the generalformula (X), in which

-   -   R² represents hydrogen,    -   compounds of the general formula (XIIIa)    -   in which    -   R¹, R³, R⁴ and R⁵ are as defined above    -   R¹⁴ represents (C₁-C₆)-alkyl, preferably methyl or ethyl,    -   are reacted with bases, such as, for example, alkali metal        hydroxides, such as sodium hydroxide, lithium hydroxide or        potassium hydroxide, or alkali metal carbonates, such as cesium        carbonate, sodium carbonate or potassium carbonate, preferably        sodium hydroxide, in inert solvents including halogenated        hydrocarbons, such as methylene chloride, trichloromethane,        carbon tetrachloride, trichloroethane, tetrachloroethane,        1,2-dichloroethane or trichloroethylene, ethers, such as diethyl        ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane,        tetrahydrofuran, glycol dimethyl ether or diethylene glycol        dimethyl ether, alcohols, such as methanol, ethanol, n-propanol,        isopropanol, n-butanol or tert-butanol, hydrocarbons, such as        benzene, xylene, toluene, hexane, cyclohexane or mineral oil        fractions, or other solvents, such as dimethylformamide,        dimethylacetamide, dimethyl sulfoxide, acetonitrile or pyridine,        or mixture of solvents (preferred solvents being tetrahydrofuran        and/or methanol), preferably in a temperature range of from        0° C. to room temperature at atmospheric pressure.

The compounds of the general formula (X) can also be preparedanalogously to the synthesis route described for processes of compoundsof the general formula (Xa) from compounds of the general formula(XIII).

To prepare the compounds of the general formula (XIIIa), compounds ofthe general formula (XIV)

in which

-   -   R¹, R³, R⁴, R⁵ and R¹⁴ are as defined above    -   are reacted with tetrabutylammonium fluoride    -   in inert solvents including halogenated hydrocarbons, such as        methylene chloride, trichloromethane, carbon tetrachloride,        trichloroethane, tetrachloroethane, 1,2-dichloroethane or        trichloroethylene, ethers, such as diethyl ether, methyl        tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran,        glycol dimethyl ether or diethylene glycol dimethyl ether,        alcohols, such as methanol, ethanol, n-propanol, isopropanol,        n-butanol or tert-butanol, hydrocarbons, such as benzene,        xylene, toluene, hexane, cyclohexane or mineral oil fractions,        or other solvents, such as nitromethane, ethyl acetate, acetone,        dimethylformamide, dimethylacetamide, 2-butanone, dimethyl        sulfoxide, acetonitrile or pyridine (the preferred solvent being        tetrahydrofuran), preferably in a temperature range of from        0° C. to room temperature at atmospheric pressure.

To prepare the compounds of the general formula (XIV), compounds of thegeneral formula (XV)

in which

-   -   R⁵ is as defined above    -   are reacted with compounds of the general formula (XVI)    -   in which    -   R¹, R³, R⁴ and R¹⁴ are as defined above    -   in inert solvents including ethers, such as diethyl ether,        methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane,        tetrahydrofuran, glycol dimethyl ether or diethylene glycol        dimethyl ether, hydrocarbons, such as benzene, ethylbenzene,        xylene, toluene, hexane, heptane, cyclohexane or mineral oil        fractions, or other solvents, such as dimethylformamide,        dimethylacetamide, acetonitrile or pyridine, or mixtures of the        solvents, preferred solvents being diethyl ether,        tetrahydrofuran, heptane and/or ethylbenzene, if appropriate in        the presence of a base, such as, for example, alkali metal        hydroxides, such as sodium hydroxide or potassium hydroxide, or        alkali metal carbonates, such as cesium carbonate, sodium        carbonate or potassium carbonate, or sodium methoxide or        potassium methoxide, or sodium ethoxide or potassium ethoxide,        or potassium tert-butoxide, or amides, such as sodium amide,        lithium bis(trimethylsilyl)amide, lithium diisopropylamide, or        organometallic compounds, such as butyllithium or phenyllithium,        or other bases, such as sodium hydride, DBU, triethylamine or        diisopropylethylamine, preferably lithium diisopropylamide,        preferably in a temperature range of from −78° C. to room        temperature at atmospheric pressure.

The compounds of the general formula (XVI) are known or can be preparedfrom the corresponding starting materials by known methods.

To prepare the compounds of the general formula (XV), compounds of thegeneral formula (XVII)

in which

-   -   R⁵ is as defined above    -   are reacted with trimethylsilyl cyanide and zinc iodide    -   if appropriate in inert solvents including halogenated        hydrocarbons, such as methylene chloride, trichloromethane,        carbon tetrachloride, trichloroethane, tetrachloroethane,        1,2-dichloroethane or trichloroethylene, ethers, such as diethyl        ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane,        tetrahydrofuran, glycol dimethyl ether or diethylene glycol        dimethyl ether, alcohols, such as methanol, ethanol, n-propanol,        isopropanol, n-butanol or tert-butanol, hydrocarbons, such as        benzene, xylene, toluene, hexane, cyclohexane or mineral oil        fractions, or other solvents, such as nitromethane, ethyl        acetate, acetone, dimethylformamide, dimethylacetamide,        2-butanone, dimethyl sulfoxide, acetonitrile or pyridine (the        preferred solvent being tetrahydrofuran), preferably in a        temperature range of from room temperature to 100° C. at        atmospheric pressure.

The compounds of the general formula (XVII) are known or can besynthesized from the corresponding starting materials by knownprocesses.

To prepare the compounds of the general formula (XIII)

in which

-   -   R¹, R², R³, R⁴, R⁵ and R¹⁴ are as defined above,    -   compounds of the general formula (XVIII)    -   in which    -   R³, R⁴ and R⁵ are as defined above,    -   are reacted with compounds of the general formula (XIX)    -   in which    -   R¹, R² and R¹⁴ are as defined above and    -   L³ represents halogen, preferably bromine or iodine,    -   in inert solvents including ethers, such as diethyl ether,        methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane,        tetrahydrofuran, glycol dimethyl ether or diethylene glycol        dimethyl ether, hydrocarbons, such as benzene, ethylbenzene,        xylene, toluene, preferred solvents being tetrahydrofuran or        toluene, if appropriate in the presence of a base, such as, for        example, amides, such as sodium amide, lithium        hexamethyldisilazide, potassium hexamethyldisilazide, lithium        diisopropylamide or other bases, such as sodium hydride, DBU or        diisopropylethylamine, preferably sodium amide, lithium        hexamethyldisilazide, potassium hexamethyldisilazide or lithium        diisopropylamide, preferably in a temperature range of from        −78° C. to room temperature at atmospheric pressure.

The compounds of the general formulae (XVIII) and (XIX) are known or canbe synthesized from the corresponding starting materials by knownprocesses (for (XVIII) cf. M. R. Schneider, H. Ball, J. Med. Chem. 1986,29, 75-79; Robl, et al., Synthesis 1991, 56; J. Org. Chem. 1996, 61,607).

In an alternative synthesis route for preparing compounds of the generalformula (IIaa), these compounds being compounds of the general formula(IIa) in which

-   -   R¹ and R² represent hydrogen,    -   compounds of the general formula (XX)    -   in which    -   R³, R⁴, R⁵ and R¹⁴ are as defined above    -   are reacted with hydrazine. The reaction is carried out        analogously to the first step of the two-step process described        for preparing the compounds of the general formula (IIa).    -   To prepare the compounds of the general formula (XX), compounds        of the general formula (XXI)    -   in which    -   R³, R⁴, R⁵ and R¹⁴ are as defined above    -   are reacted with reducing agents. The reaction is carried out        analogously to the second step of the two-step process described        for preparing the compounds of the general formula (IIa).

To prepare the compounds of the general formula (XXI), compounds of thegeneral formula (XXII)

in which

-   -   R³, R⁴, R⁵ and R¹⁴ are as defined above    -   are reacted with fuming nitric acid, concentrated nitric acid or        nitrating acid analogously to the process described for        preparing the compounds of the general formula (VII).

The compounds of the general formula (XXII) can be synthesized from thecorresponding starting materials by the process described for thecompounds of the general formula (XIII).

In an alternative synthesis route for preparing the compounds of thegeneral formula (XX), compounds of the general formula (XXIII)

in which

-   -   R³, R⁴, R⁵ and R¹⁴ are as defined above    -   and    -   R¹⁵ represents allyl or benzyl    -   are, in the case of benzyl, reacted with reducing agents. The        reaction is carried out analogously to the second step of the        two-step process described for preparing the compounds of the        general formula (IIa).

In the case of allyl, a process with tetrakistriphenylphosphinepalladiumand N,N-dimethylbarbituric acid is used, cf. F. Garro-Helion, A.Merzouk, F. Guibe, J. Org. Chem. 1993, 58, 6109-6113.

The compounds of the general formula (XXIII) can be prepared from thecorresponding starting materials by the process described for thecompounds of the general formula (XIII).

The processes described above can be illustrated in an exemplary mannerby the formula schemes below:

The compounds of the general formula (I) according to the invention havea surprising activity spectrum which could not have been foreseen. Theyshow antiviral action against representatives of the group of the Herpesviridae, in particular against the human cytomegalovirus (HCMV).Accordingly, they are suitable for the treatment and prophylaxis ofdisorders caused by Herpes viridae, in particular of disorders caused byhuman cytomegaloviruses.

Owing to their particular properties, the compounds of the generalformula (I) can be used for preparing medicaments suitable for theprophylaxis or treatment of diseases, in particular viral disorders.

Owing to their properties, the compounds according to the invention areuseful active compounds for the treatment and prophylaxis of humancytomegalovirus infections and disorders caused by these. Areas ofindication which may be mentioned are, for example:

-   -   1) The treatment and prophylaxis of HCMV infections in AIDS        patients (retinitis, pneumonitis, gastrointestinal infections).    -   2) The treatment and prophylaxis of cytomegalovirus infections        in bone marrow and organ transplant patients suffering from HCMV        pneumonitis, HCMV encephalitis and gastrointestinal and systemic        HCMV infections, which are frequently life-threatening.    -   3) The treatment and prophylaxis of HCMV infections in neonates        and infants.    -   4) The treatment of an acute HCMV infection in pregnant women.    -   5) The treatment of an HCMV infection in immunosuppressed        patients suffering from cancer and undergoing cancer therapy.

The novel active compounds can be used on their own and, if required,also in combination with other antivirally active compounds, such as,for example, gancyclovir or acyclovir.

Descriptions of Biological Tests:

In vitro Action:

Anti-HCMV (Anti-Human Cytomegalovirus) Cytopathogenicity Tests:

The test compounds are used as 50 millimolar (mM) solutions in dimethylsulfoxide (DMSO). The reference compounds used are ganciclovir,foscarnet and cidofovir. In each case 2 μl of the 50, 5, 0.5 and 0.05 mMDMSO stock solutions are added to in each case 98 μl of cell culturemedium in row 2 A-H in duplicate, and 1:2 dilutions with in each case 50μl of medium are then made up to row 11 of the 96-well plate.

The wells in rows 1 and 12 each contain 50 μl of medium. In each case150 μl of a suspension of 1×10⁴ cells (NHDF=normal human dermalfibroblasts) (row 1 =cell control) and, for rows 2-12, a mixture ofHCMV-infected and non-infected NHDF cells (M.O.I.=0.001-0.002), i.e. 1-2infected cells per 1000 non-infected cells, are then pipetted into thewells. Row 12 (without substance) serves as virus control. The finaltest concentrations are 250-0.0005 μM. The plates are incubated at 37°C./5% CO₂ for 6 days, i.e. until all cells in the virus controls areinfected (100% cytopathogenic effect [CPE]). The wells are then fixed byadding a mixture of formalin and Giemsa's dye and stained (30 minutes),washed with doubly distilled water and dried in a drying cabinet at 50°C. The plates are then examined visually using an overhead microscope(Plaque multiplier from Technomara).

Using the test plates, the following data can be determined:

-   -   CC₅₀ (NHDF)=substance concentration in μM where, compared to the        untreated cell control, no cytostatic effects on the cells are        evident;    -   EC₅₀ (HCMV)=substance concentration in μM where the CPE        (cytopathic effect) is inhibited by 50% compared to the        untreated virus control;    -   SI (selectivity index)=CC₅₀ (NHDF)/EC₅₀ (HCMV).        In vivo Action:        HCMV Xenograft Gelfoam® Model:        Animals:

Female immunodeficient mice (16-18 g), Fox Chase SCID or Fox ChaseSCID-NOD or SCID-beige, 3-4 weeks old, are obtained from commercialbreeders (Bomholtgaard, Jackson). The animals are kept under sterileconditions (including litter and feed) in isolation units.

Virus Culture:

Human cytomegalovirus (HCMV), DavisSmith strain, is cultivated in vitroon embryonal human dermal fibroblasts (NHDF cells). Following infectionof the NHDF cells with a multiplicity of infection (M.O.I.) of 0.01, thevirus-infected cells are harvested after 5-7 days and, in the presenceof minimal essential medium (MEM), 10% fetal calf serum (FCS) with 10%DMSO, stored at −40° C. Following serial dilution of the virus-infectedcells in steps of ten, the titer is determined on 24-well plates ofconfluent NHDF cells after vital stain with Neutral Red.

Preparation of the Sponges, Transplantation, Treatment and Evaluation:

Collagen sponges (Gelfoam®; from Peasel & Lorey, order No. 40734; K. T.Chong et al., Abstracts of 39th Interscience Conference on AntimicrobialAgents and Chemotherapy, 1999, p. 439) of a size of 1×1×1 cm areinitially wetted with phosphate-buffered saline (PBS), the enclosed airbubbles are removed by degassing and the sponges are then stored inMEM+10% FCS. 3 hours after infection, 1×10⁶ virus-infected NHDF cells(infection with HCMV-Davis M.O.I.=0.01) are detached and, in 20 μl ofMEM and 10% FCS, added dropwise to a moist sponge. 12-13 hours later,the infected sponges are incubated with 25 μl PBS/0.1% BSA/1 mM DTT with5 ng/μl of basic fibroblast growth factor (bFGF). For transplantation,the immunodeficient mice are anesthetized with Avertin, the dorsal hairis removed using a dry shaver, the epidermis is opened 1-2 cm andrelaxed and the moist sponges are transplanted under the dorsal skin.The operation wound is closed using tissue adhesive. 24 hours after thetransplantation, the mice are treated perorally with substance threetimes a day (7 a.m., 2 p.m. and 7 p.m.) for a period of 8 days. The doseis 7 or 15 or 30 or 60 mg/kg of body weight, the application volume is10 ml/kg of body weight. The substances are formulated in the form of a0.5% strength-suspension in tylose with 2% DMSO. 9 days after thetransplantation and 16 hours after the last administration of substance,the animals are killed painlessly and the sponge is removed. Thevirus-infected cells are released from the sponge by digestion withcollagenase (330 U/1.5 ml) and stored in the presence of MEM, 10% fetalcalf serum, 10% DMSO at −140° C. Evaluation is carried out after serialdilution of the virus-infected cells in steps of 10 by titerdetermination on 24-well plates of confluent NHDF cells after vitalstain with Neutral Red. What is determined is the number of infectiousvirus particles after substance treatment compared to theplacebo-treated control group.

Representative activity data for the compounds according to theinvention are given in Table 1: TABLE 1 NHDF HCMV Murine xenograft modelExample CC50 EC50 SI ED50 [mg]kg] No. [μM] [μM] HCMV t.i.d. 1 125 0.96130 18 2 23 0.07 329 n.d. 3 24 0.13 185 n.d. 4 >23 0.15 >153  8 5 1256.10 21 n.d.

The novel active compounds can be converted in a known manner into thecustomary formulations, such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert non-toxic, pharmaceutically acceptable carriers or solvents. Here,the therapeutically active compound should in each case be present in aconcentration of about 0.5 to 90% by weight of the total mixture, i.e.in amounts which are sufficient in order to achieve the dosage rangeindicated.

The formulations are prepared, for example, by extending the activecompounds using solvents and/or carriers, if appropriate usingemulsifiers and/or dispersants, it optionally being possible, forexample, to use organic solvents as auxiliary solvents if the diluentused is water.

Administration is carried out in a customary manner, preferably orally,parenterally or topically, in particular perlingually or intravenously.

In the case of parenteral administration, solutions of the activecompounds can be employed using suitable liquid carrier materials.

In general, it has proved advantageous in the case of intravenousadministration to administer amounts of about 0.001 to 10 mg/kg,preferably about 0.01 to 5 mg/kg, of body weight, to achieve effectiveresults, and in the case of oral administration, the dosage is about0.01 to 25 mg/kg, preferably 0.1 to 10 mg/kg of body weight.

In spite of this, it may be necessary to depart from the amountsmentioned, namely depending on the body weight or on the type ofadministration route, on the individual response toward the medicament,the type of its formulation and the time or interval at whichadministration takes place. Thus, in some cases it may be adequate tomanage with less than the abovementioned minimum amount, while in othercases the upper limit mentioned has to be exceeded. In the case of theadministration of relatively large amounts, it may be advisable todivide these into several individual doses over the course of the day.Abbreviations: abs. absolute Ac acetyl acac acetylacetonyl AIBNα,α′-azobis(isobutyronitrile) Aloc allyloxycarbonyl aq. aqueous 9-BBN9-borabicyclo[3.3.1]nonane Bn benzyl Boc tert-butoxycarbonyl Bombenzyloxymethyl BOP benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate Bu butyl Bz benzoyl CAN cerium ammonium nitrate Cbzbenzyloxycarbonyl CDI N,N′-carbonyldiimidazole CH cyclohexane Cpcyclopentadienyl CSA 10-camphorsulfonic acid Dabco1,4-diazabicyclo[2.2.2]octane DAST diethylaminosulfur trifluoride DBN1,5-diazabicyclo[4.3.0]non-5-ene DBU 1,8-diazabicyclo[5.4.0]undec-7-eneTLC thin-layer chromatography DCC N,N′-dicyclohexylcarbodiimide DCE1,2-dichloroethane DCI direct chemical ionization (MS) DCMdichloromethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DEADdiethyl azodicarboxylate d.e. diastereomeric excess dist. distilled DHP3,4-dihydro-2H-pyran DIAD diisopropyl azodicarboxylate DIBAHdiisobutylaluminum hydride DIC diisopropylcarbodiimide DIEAN,N-diisopropylethylamine DMA N,N-dimethylacetamide DMAP4-N,N-dimethylaminopyridine DME 1,2-dimethoxyethane DMFN,N-dimethylformamide DMPU N,N′-dimethylpropyleneurea DMSO dimethylsulfoxide DNPH 2,4-dinitrophenylhydrazine DPPA diphenylphosphoryl azideEDC N′-(3-dimethylaminopropyl)-N- ethylcarbodiimide × HCl e.e.enantiomeric excess EA ethyl acetate EI electron impulse ionization (MS)eq equivalent(s) ESI electrospray ionization (MS) Et ethyl liq. liquidFmoc fluorenylmethoxycarbonyl m.p. melting point fr. fraction GC gaschromatography sat. saturated HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate HBTUO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphateHMDS 1,1,1,3,3,3-hexamethyldisilazane HMPA or HMPT hexamethylphosphorictriamide HOBt 1-hydroxy-1H-benzotriazole × H₂O HOSu N-hydroxysuccinimideHPLC high pressure, high performance liquid chromatography Imimidazol-1-yl IR infrared spectroscopy conc. concentrated b.p. boilingpoint cryst. crystalline/crystallized LAH lithium aluminum hydride LC-MSliquid-chromatography-coupled mass spectroscopy LDA lithiumN,N-diisopropylamide LiHMDS lithium N,N-bistrimethylsilylamide lit.literature (reference) sol. solution m meta mCPBA meta-chloroperbenzoicacid Me methyl MEK methyl ethyl ketone MEM methoxyethoxymethyl MWmolecular weight MOM methoxymethyl MPLC medium-pressure liquidchromatography Ms methanesulfonyl (mesyl) MS mass spectroscopy MTBEmethyl tert-butyl ether NBS N-bromosuccinimade NCS N-chlorosuccinimideprec. precipitate NIS N-iodosuccinimide NMM N-methylmorpholine NMON-methylmorpholine N-oxide NMR nuclear magnetic resonance spectroscopy oortho p para p.a. pro analysi PCC pyridinium chlorochromate PDCpyridinium dichromate Pfp pentafluorophenyl Ph phenyl Piv pivaloyl PMBp-methoxybenzyl PNB p-nitrobenzyl PPA polyphosphoric acid PPTSpyridinium p-toluenesulfonate Pr propyl PS polystyrene (resin) pypyridine PyBOP benzotriazol-1-yloxy-tris(pyrrolidino)phoshoniumhexafluorophosphate RF reflux R_(f) retention index (TLC) RP reversephase (HPLC) RT room temperature R_(t) retention time (HPLC) SEM2-(trimethylsilyl)ethoxymethyl subl. sublimed TBAF tetrabutylammoniumfluoride TBAI tetrabutylammonium iodide TBDMS tert-butyldimethylsilylTBDPS tert-butyldiphenylsilyl TBTUO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate TEAtriethylamine techn. technical grade Teoc2-(trimethylsilyl)ethoxycarbonyl TES triethylsilyl Tftrifluoromethanesulfonyl TFA trifluoroacetic acid TFAA trifluoroaceticanhydride TfOH trifluoromethanesulfonic acid THF tetrahydrofuran THPtetrahydropyranyl TIPS triisopropylsilyl titr. titrated TMEDAN,N,N′,N′-tetramethylethylenediamine TMOF trimethyl orthoformate TMStrimethylsilyl TPP triphenylphosphine TPPO triphenylphosphine oxide Trttrityl Ts p-toluenesulfonyl (tosyl) TsOH p-toluenesulfonic acid v/vvolume-to-volume ratio (of a solution) dil. diluted cf. compare vol.volume w/w weight-to-weight ratio (of a solution) aq. aqueous Zbenzyloxycarbonyl decomp. decompositionStarting Materials:General Procedure [A]:Synthesis of TMS-cyanohydrins

Under an atmosphere of argon, in a 100 ml three-necked flask driedthoroughly by heating, a spatula tip of anhydrous zinc iodide is addedto 55 mmol of trimethylsilyl cyanide. At RT, 50 mmol of the liquidaldehydes are slowly added dropwise (exothermic reaction) (solidaldehydes are added a little at a time as a solid at 60° C.). Theresulting brown reaction mixture is heated at 95° C. for 7-8 hours. Theproduct is then distilled under high vacuum in a kugelrohr oven. Theresulting colorless or slightly yellow liquids are used without furtherpurification for the subsequent reactions.

The following compounds were prepared according to this procedure:

EXAMPLE 1A Phenyl[(trimethylsilyl)oxy]acetonitrile

5.63 g (55 mmol) of trimethylsilyl cyanide and 5.31 g (50 mmol) ofbenzaldehyde give 8.80 g (86% of theory) of product.

HPLC (method 3): R_(t)=3.38 min

MS (DCI): m/z=223 (M+NH₄)⁺

EXAMPLE 2A 4-Chlorophenyl[(trimethylsilyl)oxy]acetonitrile

5.63 g (55 mmol) of trimethylsilyl cyanide and 7.03 g (50 mmol) of4-chlorobenzaldehyde give 10.84 g (90% of theory) of product.

HPLC (method 1): R_(t)=3.96 min

MS (ESIpos): m/z=239 (M+H)⁺

EXAMPLE 3A 4-Methoxyphenyl[(trimethylsilyl)oxy]acetonitrile

5.63 g (55 mmol) of trimethylsilyl cyanide and 6.81 g (50 mmol) of4-methoxybenzaldehyde give 10.23 g (87% of theory) of product.

HPLC (method 3): R_(t)=3.56 min

MS (El): m/z=235 (M)⁺

General Procedure [B]:

Reaction of TMS-cyanohydrins with methyl 3-methyl-2-butenoate

1 eq. of the TMS-cyanohydrin in question is, in a 250 ml three-neckedflask which was thoroughly dried by heating, dissolved under argon inabsolute diethyl ether, and the resulting solution is cooled to −78° C.1.05 eq. of 2 M LDA solution in THF/heptane/ethylbenzene are addeddropwise over a period of 30 min. The mixture is stirred at thistemperature for another 30 min, and 1 eq. of methyl3-methyl-2-butenoate, dissolved in a little absolute diethyl ether, isthen added dropwise. Over a period of 5 hours, the mixture is allowed towarm to 0° C.-10° C. Saturated ammonium chloride solution is then added,and the mixture is stirred for 10 min. The phases are separated and theethereal phase is washed two more times with saturated ammonium chloridesolution. After drying over magnesium sulfate and filtration, thesolvent is removed on a rotary evaporator, giving the product which isused without further purification for the next synthesis step.

The following compounds were prepared according to this procedure:

EXAMPLE 4A Methyl4-cyano-3,3-dimethyl-4-phenyl-4-[(trimethylsilyl)oxy]butanoate

8.80 g (43 mmol) of phenyl[(trimethylsilyl)oxy]acetonitrile, afterdeprotonation with 22.5 ml of 2 M LDA solution, and 5.04 g (43 mmol) ofmethyl 3-methyl-2-butenoate give 13.69 g (67% of theory) of the titlecompound as crude product.

HPLC (method 3): R_(t)=5.53 min

MS (DCI): m/z=337 (M+NH₄)⁺

EXAMPLE 5A Methyl4-(4-chlorophenyl)-4-cyano-3,3-dimethyl-4-[(trimethylsilyl)oxy]butanoate

4.80 g (20 mmol) of 4-chlorophenyl[(trimethylsilyl)oxy]acetonitrile,after deprotonation with 10.5 ml of 2 M LDA solution, and 2.28 g (20mmol) of methyl 3-methyl-2-butenoate give 7.48 g (76% of theory) of thetitle compound as crude product.

HPLC (method 3): R_(t)=5.64 min

MS (DCI): m/z=371 (M+NH₄)⁺

EXAMPLE 6A Methyl4-cyano-4-(4-methoxyphenyl)-3,3-dimethyl-4-[(trimethylsilyl)oxy]butanoate

10.23 g (43.5 mmol) of4-methoxyhphenyl[(trimethylsilyl)oxy]acetonitrile, after deprotonationwith 22.8 ml of 2 M LDA solution, and 4.96 g (43.5 mmol) of methyl3-methyl-2-butenoate give 14.60 g (96% of theory) of the title compoundas crude product.

MS (DCI): m/z=367 (M+NH₄)⁺

General procedure [C]:

Desilylation with TBAF

Under an atmosphere of argon, 1 eq. of the methyl butanoate derivativesis dissolved in absolute THF (0.25 M) and cooled to 0° C. At thistemperature, 1.1 eq. of a 1 M TBAF solution in THF are slowly addeddropwise. The mixture is stirred for another 3 hours, water is thenadded and the mixture is extracted 3× with dichloromethane. After dryingover magnesium sulfate, filtration and removal of the solvent, theproduct is purified by column chromatography (silica gel: mobile phasecyclohexane/ethyl acetate=85:15) or by kugelrohr distillation.

The following compounds were prepared according to this procedure:

EXAMPLE 7A Methyl 3,3-dimethyl-4-oxo-4-phenylbutanoate

13.44 g (42 mmol) of methyl4-cyano-3,3-dimethyl-4-phenyl-4-[(trimethylsilyl)oxy]-butanoate and 46.3ml (46.3 mmol) of a 1 M TBAF solution give 6.54 g (62% of theory) of thetitle compound as crude product.

HPLC (method 3): R_(t)=4.25 min

MS (DCI): m/z=238 (M+N₄)⁺

Alternative Synthesis Method:

48.4 ml (24.20 mmol; 0.5 M solution in toluene) of potassiumhexamethyldisilazide are dissolved in 30 ml of tetrahydrofuran and, at−78° C., 3.26 g (22 mmol) of isobutyrophenone in 10 ml oftetrahydrofuran are added. After 2 hours, 4.04 g (26.40 mmol) of methylbromoacetate are added. After a further 2 hours, 50 ml of 1Nhydrochloric acid are added. The mixture is then extracted with ethylacetate. The combined organic phases are washed with water and saturatedsodium chloride solution and dried with magnesium sulfate, and thesolvent is removed. Preparative normal-phase HPLC (column: silica gel,flow rate: 150 ml/min, mobile phase: isohexane/ethyl acetate=9:1) givesthe target compound in a yield of 26%.

HPLC (method 3) R_(t)=4.60 min

MS (DCI/NH₃): m/z=238 (M+NH₄)⁺

The following examples are prepared according to the General Procedure[C]:

EXAMPLE 8A Methyl 4-(4-chlorophenyl)-3,3-dimethyl-4-oxobutanoate

6.15 g (17.4 mmol) of methyl4-(4-chlorophenyl)-4-cyano-3,3-dimethyl-4-[(trimethylsilyl)oxy]butanoateand 19.1 ml (19.1 mmol) of a 1 M TBAF solution give 4.79 g (90% oftheory) of the title compound as crude product.

HPLC (method 3): R_(t)=4.64 min

MS (DCI): m/z=272 (M+NH₄)⁺

EXAMPLE 9A Methyl 4-(4-methoxyphenyl)-3,3-dimethyl-4-oxobutanoate

14.48 g (41.4 mmol) of methyl4-cyano-4-(4-methoxyphenyl)-3,3-dimethyl-4-[(trimethylsilyl)oxy]butanoateand 45.6 ml (45.6 mmol) of a 1 M TBAF solution give 5.45 g (42% oftheory) of the title compound as crude product.

HPLC (method 3): R_(t)=4.24 min

MS (ESIpos): m/z=251 (M+H)⁺

General Procedure [D]:

Ester Hydrolysis

The ester to be hydrolyzed is dissolved in a THF/methanol mixture (1:1),and the solution is cooled to 0° C. At this temperature, 2 eq. of 1Naqueous sodium hydroxide solution are slowly added dropwise. After thereaction has ended (the reaction is monitored by TLC), in each caseidentical portions of a 1N aqueous sodium hydroxide solution anddichloromethane are added. The organic phase is extracted twice with 1Naqueous sodium hydroxide solution. The combined aqueous phases are thenacidified with concentrated hydrochloric acid and the product isextracted three times with dichloromethane. Drying over sodium sulfate,filtration and evaporation of the solvent give the product, which isused without further purification for the next synthesis step.

The following compounds were prepared according to this procedure:

EXAMPLE 10A 5-Hydroxy-4,4-dimethyl-5-phenyldihydro-2(3H)-furanone

6.52 g (29.6 mmol) of methyl 3,3-dimethyl-4-oxo-4-phenylbutanoate give5.20 g (83% of theory) of product.

HPLC (method 3): R_(t)=3.88 min

MS (DCI): m/z=224 (M+NH₄ ⁾⁺

EXAMPLE 11A5-(4-Chlorophenyl)-5-hydroxy-4,4-dimethyldihydro-2(3H)-furanone

5.11 g (20 mmol) of methyl4-(4-chlorophenyl)-3,3-dimethyl-4-oxobutanoate give 3.60 g (72% oftheory) of product.

HPLC (method 3): R_(t)=4.22 min

MS (DCI): m/z=258 (M+NH₄)⁺

EXAMPLE 12A5-Hydroxy-5-(4-methoxyphenyl)-4,4-dimethyldihydro-2(3H)-furanone

5.22 g (20.9 mmol) of methyl4-(4-methoxyphenyl)-3,3-dimethyl-4-oxobutanoate give 4.97 g (97% oftheory) of product.

HPLC (method 3): R_(t)=3.95 min

MS (ESIpos): m/z=237 (M+H)⁺

General Procedure [E]:

Friedel-Crafts Acylation of Aromatic Compounds with CarboxylicAnhydrides

Under argon, aluminum trichloride (2.4 eq.) is initially charged in athree-necked flask fitted with reflux condenser, and 1,2-dichloroethane(20 ml per g of aluminum trichloride) is added at RT. In an ice-bath,the suspension is cooled to 0° C., and the anhydride (1.05 eq.) is thenadded a little at a time. After the addition has ended, stirring iscontinued for 5 min and benzene (1.0 eq.) is then slowly added dropwise.Overnight, the mixture is slowly warmed to room temperature and thenpoured on ice, and the precipitate is redissolved in 1N hydrochloricacid. The aqueous phase is extracted 2× with dichloromethane, thecombined organic phases are washed 2× with water and dried over sodiumsulfate and the solvent is removed under reduced pressure. The substanceis used as crude product for subsequent reactions.

The following compounds were prepared according to following procedure:

EXAMPLE 13A 2,3-Dimethyl-4-oxo-4-phenylbutanoic acid

1.4 g of benzene and 2.46 g of 2,3-dimethylbutanedicarboxylic anhydridegive 0.3 g (12% of theory) of product.

HPLC (method 6): R_(t)=3.42 min

MS(ESI-POS): m/z=207 (M+H⁺)

EXAMPLE 14A 2,2-Dimethyl-4-oxo-4-phenylbutanoic acid

5.8 g of benzene and 10.0 g of 2,2-dimethylbutanedicarboxylic anhydridegive 12.6 g, (82% of theory) of product.

m.p.: 174° C.

HPLC (method 3): R_(t)=3.91 min

MS (DCI): m/z=207 (M+H⁺), 224 (M+NH₄)⁺

EXAMPLE 15A cis-2-Benzoylcyclohexanecarboxylic acid

10.0 g of benzene and 20.7 g of cis-cyclohexane-1,2-carboxylic anhydridegive 19.7 g (60% of theory) of product as a mixture of enantiomers.

HPLC (method 8): R_(t)=2.89 min

MS (ESI-POS): m/z=233 (M+H⁺)

EXAMPLE 16A trans-2-Benzoylcyclohexanecarboxylic acid

4.8 g of benzene and 10.0 g of trans-cyclohexane-1,2-carboxylicanhydride give 3.75 g (45.5% of theory) as a mixture of enantiomers.

HPLC (method 8): R_(t)=2.91 min

MS (ESI-POS): m/z=233 (M+H⁺)

EXAMPLE 17A Ethyl 3,3-dimethyl-4-phenyl-4-oxobutanoate

38.20 g (489.55 mmol) of sodium amide are initially charged in 300 ml oftoluene, and 32.98 g (222.52 mmol) of isobutyrophenone in 50 ml oftoluene are added dropwise at room temperature. After 3 h, 50.00 g(233.65 mmol) of ethyl iodoacetate in 50 ml of toluene are addeddropwise at 0° C., and the mixture is stirred for another 2 h. 500 ml ofice-water are then added, and the mixture is extracted with ethylacetate. The organic phase is washed with saturated sodium chloridesolution. After drying over magnesium sulfate, the solution isconcentrated and the residue is distilled at 152-158° C. (10 mbar). Thisgives 36.7 g (70%) of the target compound.

LCMS (method 10): R_(t)=2.93 min

MS (ESIpos): m/z=235 (M+H)⁺

EXAMPLE 18A 3,3-Dimethyl-4-oxo-4-phenylbutanoic acid and5-hydroxy-4,4-dimethyl-5-phenyl-dihydro-2(3H)-furanone

12 g (51.22 mmol) of ethyl 3,3-dimethyl-4-phenyl-4-oxobutanoate areinitially charged in 60 ml of tetrahydrofuran and 60 ml of methanol and,at room temperature, stirred with 4.10 g (102.44 mmol) of aqueous sodiumhydroxide solution for 2 hours. The solvent is distilled off, and theresidue is then acidified with 2N hydrochloric acid. The product isfiltered off with suction and recrystallized from water/ethanol.

This gives 8.90 g (84%) of the target compound as a mixture.

LC-MS (method 10): R_(t)=2.31 min

MS (ESIpos): m/z=207 (M+H)⁺

General Procedure [F]:

Nitration of Aromatic Compounds

Under argon, fuming nitric acid is cooled in a flask to −15° C., and atthis temperature, the aromatic compound is added a little at a time (300mg per 1 ml of nitric acid) in an argon countercurrent. After 30 min,the mixture is poured onto ice and extracted 2× with dichloromethane.The combined organic phases are washed 2× with water and dried oversodium sulfate, and the solvent is removed under reduced pressure. Theproduct is obtained as a mixture of the m-isomer with the p-isomerand/or the o-isomer and is reacted further without further purification.

The following compounds are prepared according to this procedure:

EXAMPLE 19A 2,3-Dimethyl-4-(3-nitrophenyl)-4-oxobutanoic acid

300 mg of 2,3-dimethyl-4-(phenyl)-4-oxobutanoic acid give 280 mg ofcrude product.

HPLC (method 8): R_(t)=2.43 min, 2.46 min (mixture of diastereomers)

MS (ESI-POS): m/z=252 (M+H⁺)

EXAMPLE 20A 2,2-Dimethyl-4-(3-nitrophenyl)-4-oxobutanoic acid

5.0 g of 2,2-dimethyl-4-(phenyl)-4-oxobutanoic acid give 5.1 g (83.9% oftheory) of product.

HPLC (method 3): R_(t)=3.95 min

MS (DCI): m/z=252 (M+H⁺), 269 (M+NH₄)⁺

EXAMPLE 21A cis-2-(3-Nitrobenzoyl)cyclohexanecarboxylic acid

5.0 g of the cis 2-benzoylcyclohexanecarboxylic acid give 5.0 g of crudeproduct as a mixture of enantiomers.

HPLC (method 6): R_(t)=3.66 min, 3.74 min (m- and p-product)

MS (ESI-POS): m/z=278 (M+H⁺)

EXAMPLE 22A trans-2-(3-Nitrobenzoyl)cyclohexanecarboxylic acid

3.75 g of trans-2-benzoylcyclohexanecarboxylic acid give 3.5 g of crudeproduct as a mixture of enantiomers.

HPLC (method 8): R_(t)=2.54 min, 2.62 min (m- and p-product)

MS (ESI-POS): m/z=278 (M+H⁺)

EXAMPLE 23A5-Hydroxy-4,4-dimethyl-5-(3-nitrophenyl)dihydro-2(3H)-furanone and3,3-dimethyl-4-(3-nitrophenyl)-4-oxobutanoic acid

8.65 g (41.94 mmol) of a mixture of 3,3-dimethyl-4-oxo-4-phenylbutanoicacid and 5-hydroxy-4,4-dimethyl-5-phenyldihydro-2(3H)-furanone areinitially charged in 20 ml of sulfuric acid, and 5.49 g of nitric acid(65% strength) in 10 ml of sulfuric acid are added at −15° C. Stirringis continued at 0° C. for 1 hour. Ice-water is then added, and themixture is extracted with ethyl acetate. The combined organic phases arewashed with water and dried over magnesium sulfate. After removal of thesolvent, the product mixture crystallizes out. The yield is 10.5 g(quantitative).

LC-MS (method 6): R_(t)=3.40/3.50 min

MS (ESIneg): m/z=250 (M−H)⁻

EXAMPLE 24A5-Hydroxy-4,4-dimethyl-5-(3-nitrophenyl)dihydro-2(3H)-furanone and5-hydroxy-4,4-dimethyl-5-(4-nitrophenyl)dihydro-2(3H)-furanone

In a flask, fuming nitric acid (12 ml) is, under argon, cooled to −15°C. At this temperature, 5 g (24.5 mmol) of5-hydroxy-4,4-dimethyl-5-phenyldihydro-2(3H)-furanone are added a littleat a time as a solid. Stirring is continued at −15° C. for half an hourand the mixture is then poured onto ice and extracted three times withdichloromethane. The combined extracts are dried over magnesium sulfate.Purification is carried out by column chromatography(dichloromethane/methanol 97:3). This gives 6.23 g of a product mixtureof the title compounds as crude product.

HPLC (method 3): R_(t)=4.06 min

MS (DCI): m/z=269 (M+NH₄)⁺

EXAMPLE 25A5-(4-Chloro-3-nitrophenyl)-5-hydroxy-4,4-dimethyldihydro-2(3H)-furanone

In a flask, fuming nitric acid (7 ml) is, under argon, cooled to −15° C.At this temperature, 3.42 g (14.2 mmol) of5-(4-chlorophenyl)-5-hydroxy-4,4-dimethyldihydro-2(3H)-furanone areadded a little at a time as a solid. Stirring at −15° C. is continuedfor 45 min (until the entire solid has gone into solution) and themixture is then poured onto ice and extracted three times withdichloromethane. The combined extracts are dried over sodium sulfate.After filtration and removal of the solvent, the residue is dried underhigh vacuum. This gives 3.89 g (87% of theory, purity 91%) of product.

HPLC (method 3): R_(t)=4.20 min

MS (DCI): m/z=303 (M+NH₄)⁺

EXAMPLE 26A5-Hydroxy-5-(4-methoxy-3-nitrophenyl)-4,4-dimethyldihydro-2(3H)-furanone

Since 5-hydroxy-5-(4-methoxyphenyl)-4,4-dimethyldihydro-2(3H)-furanoneis not obtained as a solid but as a relatively viscous oil, the fumingnitric acid is, at −15° C., slowly added to the substance. After a shortperiod of time, a vigorous reaction (evolution of nitrous gases) setsin. Stirring is continued for 30 min and the mixture is then poured ontoice and extracted three times with dichloromethane. This gives 5.65 g ofthe title compound as a crude product. The crude product is, withoutfurther work-up, used for subsequent reactions.

MS (DCI): m/z=299 (M+NH₄)⁺

General Procedure [G]:

Cyclization to the Pyridazinone and Simultaneous Reduction of a NitroGroup

The nitro compound (1.0 eq.) and hydrazine monohydrate (20.0 eq.) are,at RT, initially charged in ethanol (0.1 M solution), 10% by weight ofpalladium/carbon (10% by weight) are then added and the mixture isheated under reflux overnight. The catalyst is then filtered off andwashed with ethanol and the solvent is subsequently removed underreduced pressure. The product is purified by repeated recrystallizationfrom ethanol or by column chromatography (silica gel for removing theo-isomer, preparative HPLC (method 12) for removing the p-isomer).

The following compounds were prepared according to this procedure:

EXAMPLE 27A6-(3-Aminophenyl)-4,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone

500 mg of 2,3-dimethyl-4-(3-nitrophenyl)-4-oxobutanoic acid give 210 mgof crude product which is reacted further without further purification.

HPLC (method 6): R_(t)=0.85 min; 1.10 min (mixture of diastereomers)

MS (ESI-POS): m/z=218 (M+H⁺)

EXAMPLE 28A 6-(3-Aminophenyl)-4,4-dimethyl-4,5-dihydro-3(2H)-pyridazinone

4.95 g of 2,2-dimethyl-4-(3-nitrophenyl)-4-oxobutanoic acid give 1.24 g(28% of theory) of product.

HPLC (method 3): R_(t)=2.90 min

MS (ESI-POS): m/z=218 (M+H⁺)

During chromatography, the o-isomer could be isolated as a by-product(HPLC method 3: R_(t)=3.10 min)

EXAMPLE 29A4-(3-Aminophenyl)-cis-4a,5,6,7,8,8a-hexahydro-1(2H)-phthalazinone

500 mg of cis-2-(3-nitrobenzoyl)cyclohexanecarboxylic acid give, inquantitative yield, the target compound as crude product which isreacted without further purification.

HPLC (method 6): R_(t)=2.32 min, 2.55 min, 3.34 min, 3.40 min

MS (ESI-POS): all m/z=244 (M+H⁺)

EXAMPLE 30A4-(3-Aminophenyl)-trans-4a,5,6,7,8,8a-hexahydro-1(2H)-phthalazinone

3.5 g of crude product trans-2-(3-nitrobenzoyl)cyclohexanecarboxylicacid give, in quantitative yield, the target compound as crude productwhich is reacted without further pufication.

HPLC (method WTB): R_(t)=1.91 min

EXAMPLE 31A6-(3-Aminophenyl)-5,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone and6-(4-amino-phenyl)-5,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone

2.98 g (11.9 mmol) of a mixture of5-hydroxy-4,4-dimethyl-5-(3-nitrophenyl)dihydro-2(3H)-furanone and5-hydroxy-4,4-dimethyl-5-(4-nitrophenyl)-dihydro-2(3H)-furanone aredissolved in 40 ml of ethanol at RT, and 8.91 g (178 mmol) of hydrazinemonohydrate are added. This is followed by the addition of 300 mg ofpalladium/carbon (10% by weight), and the reaction mixture is heated atreflux for 20 hours. The hot reaction mixture is then filtered throughCelite, the filter cake is washed with hot ethanol and the filtrate isconcentrated to dryness. The residue is crystallized from ethanol. Thisgives 1.09 g (34% of theory) of a product mixture comprising 80% ofmeta- and 20% of para-product. Recrystallization from the mother liquorgives 1.03 g (30% of theory) of a product mixture comprising 74% ofpara- and 26% of meta-product. The two fractions are combined and para-and meta-product are separated by preparative HPLC (method 12).

HPLC (method 3): R_(t)=2.53 min (para) and 2.83 min (meta)

MS (EI): m/z=217 (M)⁺

EXAMPLE 32A6-(3-Amino-4-chlorophenyl)-5,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone

3.86 g (13.5 mmol) of5-(4-chloro-3-nitrophenyl)-5-hydroxy-4,4-dimethyldihydro-2(3H)-furanoneare dissolved in 40 ml of ethanol at RT, and 10.14 g (203 mmol) ofhydrazine monohydrate are added. This is followed by the addition of 350mg of palladium/carbon (10%), and the reaction mixture is heated atreflux for 24 hours. The hot reaction mixture is then filtered throughCelite, the filter cake is washed with hot ethanol and the filtrate isconcentrated to dryness. The residue is crystallized from ethanol. Thisgives 1.66 g (48% of theory) of product. Crystallization from the motherliquor gives another 0.34 g (10% of theory) of product.

HPLC (method 3): R_(t)=3.56 min

MS (DCI): m/z=269 (M+NH₄)⁺

EXAMPLE 33A6-(4-Methoxy-3-nitrophenyl)-5,5-dimethyl-4,5-dihydro-3-(2H)-pyridazinone

5.40 g (19.2 mmol) of5-hydroxy-5-(4-methoxy-3-nitrophenyl)-4,4-dimethyldihydro-2(3H)-furanoneare dissolved in 60 ml of absolute ethanol at RT, 3.84 g (77 mmol) ofhydrazine monohydrate are added and the mixture is heated at reflux for6 hours. Removal of the solvent results in the precipitation of a brownsolid which is filtered off and dried. Drying under high vacuum gives1.80 g (34% of theory) of product.

HPLC (method 3): R_(t)=3.80 min

MS (DCI): m/z=295 (M+NH₄)⁺

EXAMPLE 34A6-(3-Amino-4-methoxyphenyl)-5,5-dimethyl-4,5-dihydro-3-(2H)-pyridazinone

1.77 g (6.4 mmol) of6-(4-methoxy-3-nitrophenyl)-5,5-dimethyl-4,5-dihydro-3-(2H)-pyridazinoneare dissolved in 50 ml of absolute ethanol at RT, and 3.20 g (64 mmol)of hydrazine monohydrate and 170 mg of palladium/carbon (10% by weight)are added. The reaction mixture is heated at reflux for 10 hours andthen concentrated and purified by column chromatography (ethylacetate/cyclohexane 7:3). This gives 0.7 g (24% of theory) of the titlecompound.

HPLC (method 3): R_(t)=2.91 min

MS (EI): m/z=247 (M)⁺

EXAMPLE 35A6-(3-Amino-4-methylphenyl)-5-ethyl-5-methyl-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 36A from 15.00 g (53.71 mmol) of5-ethyl-5-methyl-6-(4-methyl-3-nitrophenyl)-4,5-dihydro-3(2H)-pyridazinoneand 26.89 g (537.08 mmol) of hydrazine hydrate in a yield of 82%.

¹H-NMR (200 MHz, DMSO): δ=0.72 (t, 3H), 1.12 (s, 3H), 1.35-1.80 (m, 2H),2.05 (s, 3H), 2.30 (q, 2H), 3.33 (s, 1H), 4.89 (br.s, 2H), 6.50 (dd,1H), 6.68 (d, 1H), 6.88 (d, 1H), 10.83 (br.s, 1H).

EXAMPLE 36A5-Ethyl-6-(3-isocyanato-4-methylphenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone

4.91 g (20 mmol) of6-(3-amino-4-methylphenyl)-5-ethyl-5-methyl-4,5-dihydro-3(2H)-pyridazinoneare initially charged in 200 ml of dichloromethane and, at 0° C.,initially 8.57 g (40 mmol) of 1,8-bis-(dimethylamino)naphthalene andthen 2.85 g (14.40 mmol) of trichloromethyl chloroformate in 80 ml ofdichloromethane are added. After 1 hour at room temperature, the mixtureis diluted with 50 ml of dichloromethane. The organic phase is washedwith ice-water, 1N hydrochloric acid and saturated sodium chloridesolution and dried over magnesium sulfate. After concentration of thesolution and trituration of the residue with n-heptane, the targetcompound is isolated in a yield of 5.30 g (98%).

MS (DCI/NH₃): m/z=272 (M+H⁺)

EXAMPLE 37A (4-Bromophenyl)-[(trimethylsilyl)oxy]acetonitrile

According to a procedure of K. Deuchert, U. Hertenstein, S. Hünig, G.Wehner, Chem. Ber. 1979, 112, 2045-2061, under an atmosphere of argon, asmall spatula tip of zinc iodide is added as catalyst to 2.73 g (27.5mmol) of trimethylsilyl cyanide, and the mixture is heated to 60° C. Atthis temperature, 4.23 g (25 mmol) of 4-bromo-benzaldehyde are added alittle at a time as a solid. The temperature is then increased to 95° C.and maintained at this level for 8 hours. Purification is then carriedout by kugelrohr distillation under high vacuum (220-230° C.). Thisgives 6.11 g (85% of theory) of product as a yellow oil.

HPLC (method 3): R_(t)=3.88 min

MS (ESIpos): m/z=306 (M+Na)⁺

EXAMPLE 38A Methyl4-(4-bromophenyl)-4-cyano-3,3-dimethyl-4-[trimethylsilyl)oxy]butanoate

According to a procedure from S. Hünig, G. Wehner, Chem. Ber. 1980, 113,302-323, 6 g (21.11 mmol) of(4-bromophenyl)-[(trimethylsilyl)oxy]acetonitrile are, under anatmosphere of argon, dissolved in 21 ml of dry diethyl ether, and theresulting solution is cooled to −78° C. Over a period of 20 min, 11.1 ml(22.2 mmol) of a 2-molar solution of lithium diisopropylamide are addeddropwise. After 30 min, a solution of 2.48 g (21.11 mmol) of methyl3-methyl-2-butenoate in 2 ml of dry diethyl ether is added dropwise. Ina cooling bath, the reaction mixture is, over a period of 4-5 hours,slowly allowed to warm to room temperature. 40 ml of saturated ammoniumchloride solution are then added, and stirring is continued at roomtemperature for 10 min. The phases are separated and the organic phaseis dried over magnesium sulfate. Filtration and evaporation of thesolvent give 9.48 g of crude product which is used without furtherpurification for the next synthesis.

HPLC (method 1): R_(t)=5.72 min

MS (EI): m/z=397 (M)⁺

EXAMPLE 39A Methyl 4-(4-bromophenyl)-3,3-dimethyl-4-oxobutanoate

Under an atmosphere of argon, 8.65 g (crude product) of methyl4-(4-bromophenyl)-4-cyano-3,3-dimethyl-4-[trimethylsilyl)oxy]butanoateare dissolved in 87 ml of dry tetrahydrofuran, and the solution iscooled in an ice-bath to 0° C. At this temperature, 21.7 ml (21.7 mmol)of a 1-molar solution of tetrabutylammonium fluoride are slowly addeddropwise. After 4.5 hours at 0° C., 75 ml of water are added and themixture is extracted 3 times with dichloromethane. The combined organicphases are dried over magnesium sulfate. After filtration andevaporation of the solvent, purification is carried out by columnchromatography (silica gel: cyclohexane/ethyl acetate 85:15), giving4.25 g (57% of theory over 2 steps) of product.

HPLC (method 3): R_(t)=4.84 min

MS (EI): m/z=298 (M)⁺

EXAMPLE 40A Methyl 4-(4-bromo-3-nitrophenyl)-3,3-dimethyl-4-oxobutanoate

Under argon, 6 ml of fuming nitric acid are cooled to −30° C., and 3.71g (12.4 mmol) of methyl 4-(4-bromophenyl)-3,3-dimethyl-4-oxobutanoateare added dropwise at this temperature. Stirring at −30° C. is continuedfor 1 hour and the mixture is then poured onto ice and extracted 3 timeswith dichloromethane. The combined organic extracts are dried overmagnesium sulfate. After filtration and evaporation of the solvent, theproduct is purified by column chromatography (silica gel:cyclohexane/ethyl acetate 9:1). This gives 2.83 g (66% of theory) ofproduct as a yellow oil.

HPLC (method 3): R_(t)=4.75 min

MS (DCI): m/z=361 (M+NH₄)⁺

EXAMPLE 41A Methyl 4-(3-aminophenyl)-3,3-dimethyl-4-oxobutanoate

0.85 g (2.46 mmol) of methyl4-(4-bromo-3-nitrophenyl)-3,3-dimethyl-4-oxobutanoate is dissolved in 12ml of degassed ethanol, 131 mg of palladium on carbon (10%) are addedand the mixture is stirred under an atmosphere of hydrogen untilreaction monitoring by analytical HPLC shows complete conversion. Themixture is filtered through kieselguhr and the solvent is evaporated.The residue is taken up in ethyl acetate and washed with saturatedsodium bicarbonate solution. The organic phase is dried over magnesiumsulfate. Filtration and concentration of the solvent give 0.52 g (83% oftheory) of product which is used as crude product for further syntheses.

EXAMPLE 42A 4-(2-Hydroxy-5-nitrophenyl)-3,3-dimethyl-4-oxobutanoic acid

10.00 g (37.14 mmol) of4-(2-fluoro-5-nitrophenyl)-3,3-dimethyl-4-oxobutanoic acid and 7.02 g(83.57 mmol) of sodium bicarbonate are initially charged in 100 ml ofwater, 11.46 g (81.72 mmol) of ammonium hydroxide are added and themixture is stirred under reflux overnight. After cooling, the mixture isacidified with 1N hydrochloric acid and extracted with ethyl acetate,and the organic phase is washed with water. Drying over magnesiumsulfate and removal of the solvent by distillation is followed byrecrystallization from methylene chloride/n-pentane and drying underreduced pressure.

This gives 6.52 g (66% of theory) of product.

HPLC (method 3): R_(t)=3.90 min

MS (DCI/NH₃): m/z=285 (M+NH₄)⁺.

EXAMPLE 43A 4-(2-Cyano-5-nitrophenyl)-3,3-dimethyl-4-oxobutanoic acid

The preparation of 4-(2-cyano-5-nitrophenyl)-3,3-dimethyl-4-oxobutanoicacid is carried out using the starting material4-(2-fluoro-5-nitrophenyl)-3,3-dimethyl-4-oxobutanoic acid, similarly tothe literature references Heterocycles 1987, 26, 1227 and Synth. Commun.1985, 15, 479.

EXAMPLE 44A6-(2-Hydroxy-5-nitrophenyl)-5,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone

26.00 g (94.12 mmol) of4-(2-cyano-5-nitrophenyl)-3,3-dimethyl-4-oxobutanoic acid (Example 43A)are dissolved in 400 ml of ethanol, and 47.12 g (941.19 mmol) ofhydrazine hydrate are added dropwise under reflux. The mixture isstirred at boiling point for 5 h and the solution is then concentratedto 100 ml. Water is added to the residue and the volume is concentratedto 200 ml. The crystals are then filtered off with suction and washedwith water and diethyl ether. Drying under reduced pressure gives 20.03g (81% of theory) of product.

HPLC (method 3): R_(t)=3.50 min

MS (DCI/NH₃): m/z=281 (M+NH₄)⁺

Alternatively, using the same synthesis procedure, Example 44A can alsobe prepared from 4-(2-hydroxy-5-nitrophenyl)-3,3-dimethyl-4-oxobutanoicacid (Example 42A).

EXAMPLE 45A6-(5-Amino-2-hydroxyphenyl)-5,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone

3.00 g (11.40 mmol) of6-(2-hydroxy-5-nitrophenyl)-5,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone(Example 45A) are dissolved in 150 ml of ethanol, and 0.30 gpalladium/carbon (10%) is added. At boiling point, 5.70 g (113.96 mmol)of hydrazine hydrate are added dropwise. After 18 h of stirring underreflux, the solvent is removed and the oily residue is crystallized fromdiethyl ether. The crystals are triturated with water and filtered offwith suction. After washing with diethyl ether, the crystals are driedunder reduced pressure. This gives 1.84 g (69% of theory) of product.

HPLC (method 3): R_(t)=2.30 min

MS (ESI pos): m/z=234 (M+H)⁺

PREPARATION EXAMPLES EXAMPLE 1N-(2,4-Difluorophenyl)-N′-[3-(4,4-dimethyl-6-oxo-1,4,5,6-tetrahydro-3-pyridazinyl)-phenyl]urea

At room temperature, 2 ml of abs. THF are added to 50 mg (0.23 mmol) of6-(3-aminophenyl)-5,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone, and 71.4mg (0.46 mmol) of 2,4-difluorophenyl isocyanate are then added.Initially, the6-(3-aminophenyl)-5,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone does notdissolve completely. Only after the addition of the isocyanate is, aftera short period of time, a clear yellow solution formed; however, thissolution quickly yields a white precipitate. Stirring is continuedovernight and the precipitate is then filtered off. The precipitate iswashed with diethyl ether and the white solid is dried under reducedpressure. This gives 46.4 mg (54% of theory) of product.

m.p.: 213° C.

¹H-NMR (200 MHz, DMSO): δ=1.16 (s, 6H), 2.35 (s, 2H), 6.97-7.11 (m, 2H),7.25-7.39 (m, 3H), 7.65 (s, 1H), 7.99-8.17 (m, 1H), 8.50 (s, br 1H),9.12 (s, br 1 H), 10.99 (s, 1H).

HPLC (method 3): R_(t)=4.12 min

MS (ESIpos): m/z=373 (M+H)⁺

EXAMPLE 2N-(3-Chloro-4-fluorophenyl)-N′-[3-(4,4-dimethyl-6-oxo-1,4,5,6-tetrahydro-3-pyridazinyl)phenyl]urea

1 ml of abs. THF is added to 30 mg (0.14 mmol) of6-(3-aminophenyl)-5,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone and 47.4mg (0.28 mmol) of 3-chloro-4-fluoro-phenyl isocyanate (slightly turbidsolution), and the mixture is stirred at room temperature overnight.Formation of a white precipitate is observed.

Work-up: In each case 1 ml of dichloromethane and diethyl ether areadded to the reaction mixture, and the white precipitate is filteredoff. This gives 40.2 mg (75% of theory) of product.

¹H-NMR (200 MHz, DMSO): δ=1.16 (s, 6H), 2.35 (s, 2H), 7.04 (d, 1H),7.25-7.42 (m, 4H), 7.63 (s, 1H), 7.76-7.83 (m, 1H), 8.89 (s, 2H), 10.99(s, 1H).

HPLC (method 3): R_(t)=4.32 min

MS (ESIpos): m/z=389 (M+H)⁺

EXAMPLE 3N-(3-Bromophenyl)-N′-[3-(4,4-dimethyl-6-oxo-1,4,5,6-tetrahydro-3-pyridazinyl)-phenyl]urea

30 mg (0.14 mmol) of6-(3-aminophenyl)-5,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone aredissolved in 1 ml of absolute THF. 54.7 mg (0.28 mmol) of 3-bromophenylisocyanate are added, and the mixture is then stirred at roomtemperature overnight. This results in the precipitation of a whitesolid. Filtration gives 48.4 mg (84% of theory) of product as a whitesolid.

m.p.: 207° C.

¹H-NMR (200 MHz, DMSO): δ=1.16 (s, 6H), 2.35 (s, 2H), 6.99-7.45 (m, 6H),7.64 (s, 1H), 7.85 (s, 1H), 8.90 (s, br 2H), 10.99 (s, br 1H).

HPLC (method 3): R_(t)=4.32 min

MS (ESIpos): m/z=415 (M+H)⁺

EXAMPLE 4N-(4-Chloro-2-methylphenyl)-N′-[3-(4,4-dimethyl-6-oxo-1,4,5,6-tetrahydro-3-pyridazinyl)phenyl]urea

46.3 mg (0.28 mmol) of 4-chloro-2-methylphenyl isocyanate are initiallycharged in 1 ml of ethyl acetate (not completely soluble), 30 mg (0.14mmol) of 6-(3-aminophenyl)-5,5-dimethyl-4,5-dihydro-3(2H)-pyridazinoneare added and the mixture is stirred at room temperature overnight. Theformation of a white precipitate is observed.

Work-up: The precipitate is filtered off, washed with diethyl ether anddried under reduced pressure. Since the product is still showingimpurities, it is purified by RP-HPLC. This gives 25.6 mg (48% oftheory) of product as a white solid.

m.p.: 232° C.

¹H-NMR (200 MHz, DMSO): δ=1.16 (s, 6H), 2.24 (s, 3H), 2.35 (s, 2H),6.99-7.06 (m, 1H), 7.15-7.40 (m, 4H), 7.66 (s, 1H), 7.87 (d, 1H), 7.99(s, 1H), 9.16 (s, 1H), 10.99 (s, 1H).

HPLC (method 3): R_(t)=4.30 min

MS (ESIpos): m/z=385 (M+H)⁺

EXAMPLE 5N-(2,4-Difluorophenyl)-N′-[2-(5,5-dimethyl-6-oxo-1,4,5,6-tetrahydro-3-pyridazinyl)-phenyl]urea

20.3 mg (0.09 mmol) of6-(2-aminophenyl)-5,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone aresuspended in 1 ml of ethyl acetate, and 29 mg (0.18 mmol) of2,4-difluorophenyl isocyanate are added at room temperature. After awhile, the reaction mixture becomes completely clear and the resultingcolorless clear solution is stirred overnight. The solvent is removedusing a rotary evaporator and the residue is purified by RP-HPLC. Thisgives 26.1 mg (75% of theory) of product.

¹H-NMR (200 MHz, DMSO): δ=1.10 (s, 6H), 2.83 (s, 2H), 6.98-7.14 (m, 2H),7.24-7.40 (m, 2H), 7.43-7.50 (m, 1H), 7.82-7.96 (m, 1H), 8.02-8.09 (m,1H), 9.07 (s, 1H), 9.50 (s, 1H), 10.77 (s, 1H).

HPLC (method 3): R_(t)=4.32 min

MS (ESIpos): m/z=373 (M+H)⁺

EXAMPLE 6N-(3,4-Difluorophenyl)-N′-[3-(5,5-dimethyl-6-oxo-1,4,5,6-tetrahydro-3-pyridazinyl)-phenyl]urea

42.8 mg (0.28 mmol) of 3,4-difluorophenyl isocyanate are dissolved in0.5 ml of ethyl acetate, a solution of 30 mg (0.14 mmol) of6-(3-aminophenyl)-5,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone in 0.5 mlof ethyl acetate is added and the mixture is stirred at room temperatureovernight. The formation of a white precipitate is observed.

Work-up: The reaction mixture is concentrated and the residue ispurified by RP-HPLC. This gives 48 mg (93% of theory) of product as awhite solid.

m.p.: 200° C.

¹H-NMR (200 MHz, DMSO): δ=1.08 (s, 6H), 2.1 (s, 2H), 7.09-7.18 (m, 1H),7.26-7.44 (m, 4H), 7.60-7.74 (m, 1H), 7.97 (s, 1H), 8.89 (s, 2H), 10.90(s, 1H).

HPLC (method 3): R_(t)=4.28 min

MS (ESIpos): m/z=373 (M+H)⁺

General Procedure [H]:

Reaction of Anilines with Isocyanates

Under an atmosphere of inert gas and at room temperature, a solution of1.0 eq. of aniline in tetrafuran (0.2 M solution) is mixed with 1.2 eq.of isocyanate (dissolved in the same volume of absolutetetrahydrofuran). The reaction mixture is shaken at room temperatureovernight. Methylene chloride/diethyl ether (1:1) are added to thereaction mixture, the mixture is shaken for 1 h and the precipitatedsolid is then obtained by filtration. For purification, the solid iswashed with diethyl ether or alternatively purified either bycrystallization from methylene chloride or by preparative HPLC.

The following compounds were prepared according to this method:

EXAMPLE 7N-(2,4-Dichlorophenyl)-N′-[3-(6-oxo-1,4,5,6-tetrahydro-3-pyridazinyl)phenyl]urea

¹H-NMR (200 MHz, DMSO): δ=2.45-2.60 (m, 2H), 2.89-3.03 (m, 2H), 3.07 (s,1H), 7.15-7.50 (m, 4H), 7.96 (s, 1H), 8.14 (s, 1H), 8.23 (d, 1H), 9.33(s, 1H), 10.52 (s, 1H).

HPLC (method 3): R_(t)=4.40 min

MS (ESIpos): m/z=377 (M+H)⁺

EXAMPLE 8N-(3,4-Difluorophenyl)-N′-[3-(4-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridazinyl)phenyl]urea

¹H-NMR (200 MHz, DMSO): δ=1.10 (d, 3H), 2.26 (d, 1H), 2.60-2.80 (m, 1H),3.20-3.45 (m, 1H), 7.10-7.21 (m, 1H), 7.22-7.48 (m, 4H), 7.57-7.73 (m,1H), 7.99 (s, 1H), 8.89 (s, 2H), 10.99 (s, 1H).

HPLC (method 3): R_(t)=4.10 min

MS (DCI/NH₃): m/z=376 (M+NH₄)⁺

EXAMPLE 9N-(2,4-Difluorophenyl)-N′-[3-(4-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridazinyl)-phenyl]urea

Enantiomer A:

The target compound is prepared as a racemate from the correspondingstarting materials and then separated from the other enantiomer using anHPLC method (method 9) specifically developed for this enantiomerseparation.

¹H-NMR (200 MHz, DMSO): δ=1.10 (d, 3H), 2.25 (d, 1H), 2.61-2.80 (m, 1H),3.26-3.42 (m, 1H), 7.00-7.15 (m, 1H), 7.28-7.51 (m, 4H), 7.95-8.20 (m,2H), 8.49 (s, 1H), 9.15 (s, 1H), 10.99 (s, 1H).

HPLC (method 9): R_(t)=23.63 min

MS (DCI/NH₃): m/z=376 (M+NH₄)⁺

EXAMPLE 10N-(2,4-Difluorophenyl)-N′-[3-(4-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridazinyl)-phenyl]urea

Enantiomer B:

The target compound is prepared as a racemate from the correspondingstarting materials and then separated from the other enantiomer using anHPLC method (method 9) specifically developed for this enantiomerseparation.

¹H-NMR (200 MHz, DMSO): δ=1.10 (d, 3H), 2.25 (d, 1H), 2.61-2.80 (m, 1H),3.26-3.42 (m, 1H), 7.00-7.15 (m, 1H), 7.28-7.51 (m, 4H), 7.95-8.20 (m,2H), 8.49 (s, 1H), 9.15 (s, 1H), 10.99 (s, 1H).

HPLC (method 9): R_(t)=27.13 min

MS (DCI/NH₃): m/z=376 (M+NH₄)⁺

The examples of Table 1 can be obtained by the general procedure [H].TABLE 1 MS(ESI+) HPLC m/z Rt[min] HPLC Example No. Structure MW [M + H]⁺(%) method 11

354 355 3.48(100) 6 12

366 367 3.33(100) 6 13

372 373 3.76(100) 6 14

385 385 3.95(100) 6 15

404 405 3.95(100) 6 16

405 405 3.44(100) 6 17

435 435 3.90(100) 6 18

350 351 3.61(100) 6 19

350 351 3.60(100) 6 20

350 351 3.49(100) 6 21

354 355 3.53(100) 6 22

354 355 3.67(92) 6 23

366 367 3.43(100) 6 24

401 401 3.95(93) 6 25

404 405 3.92(100) 6 26

405 405 4.10(100) 6 27

405 405 4.02(100) 6 28

408 405 4.17(82) 6 29

372 373 3.66(100) 6 30

344 345 4.06(92) 3 31

344 345 3.90 3 32

468 468 4.10 3 33

203 MS(EI+) [M]+203 2.62 3 34

358 MS (DCI/NH3) [M + NH4]+376 4.00 3 35

382 383 3.90 3 36

565 565 4.60 3 37

382.4 383 13.64 9 38

382.4 383 13.97 9 39

422 423 4.43(100) 3 40

379 380 3.43(100) 3 41

381 382 4.12(100) 3 42

423 424 3.93(100) 3 43

361 362 3.95(100) 3 44

434 435 4.30(100) 3 45

405 405 4.47(100) 3 46

368 369 4.25(100) 3 47

422 423 4.27(100) 3 48

372 373 4.24(100) 3 49

389 389 4.39(100) 3 50

354.4 355 4.24(100) 3 51

404.4 405 4.47(100) 3 52

405.3 405 4.64(100) 3 53

368.4 369 4.36(100) 3 54

404.4 405 4.84(100) 3 55

372.4 373 4.62(100) 3 56

405.3 405 4.76(100) 3 57

388.8 389 4.64(100) 3 58

368.4 369 4.54(100) 3 59

354.4 355 3.64(100) 6 60

410.9 412 2.87(100) 8

EXAMPLE 61N-(4-Cyano-2-methylphenyl)-N′-[5-(4-ethyl-4-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridazinyl)-2-methylphenyl]urea

79.3 mg (0.60 mmol) of 4-amino-3-methylbenzonitrile are initiallycharged in 5 ml of tetrahydrofuran, and 135.66 mg (0.50 mmol) of5-ethyl-6-(3-isocyanato-4-methylphenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinoneand 1 drop of triethylamine are added. After 20 hours at 50° C., thetarget compound is filtered off with suction and washed withtetrahydrofuran and diethyl ether. The yield is 28 mg (14%).

¹H-NMR (400 MHz, DMSO): δ=0.73 (t, 3H), 1.15 (s, 3H), 1.44-1.55 (m, 1H),1.65-1.78 (m, 1H), 2.23 (d, 1H), 2.30 (s, 3H), 2.32 (s, 1H), 2.43 (d,1H), 7.02 (dd, 1H), 7.20 (dd, 1H), 7.58-7.64 (m, 2H), 7.96 (d, 1H), 8.21(d, 1H), 8.58-8.62 (m, 2H), 10.91 (s, 1H).

The examples of Table 2 can be obtained according to the generalprocedure [H]. TABLE 2 MS(ESI+) HPLC m/z Rt[min] HPLC Example No.Structure MW [M + H]⁺ (%) method 62

375 376 4.12(100) 3 63

368 389 3.78(98.9) 5 64

390 391 3.97(100) 5 65

372 373 3.82(98.9) 5 66

404 405 4.21(100) 5 67

384 385 4.43(100) 3 68

410 411 4.3(100) 3 69

400 401 4.1(100) 3 70

384 385 3.8(96.4) 3 71

386 387 4.0(96.1) 3 72

357 358 3.64(94) 3General LC-MS and HPLC Methods:HPLC Parameters:

Method 1 (HPLC):

Column: Kromasil C18, L-R

Temperature: 30° C.

Flow rate=0.75 ml/min

Mobile phase=0.01 M HClO₄, B═CH₃CN

Gradient: →0.5 min 98% A→4.5 min 10% A→6.5 min 10% A

Method 2 (HPLC):

Column: Kromasil C18 60*2, L-R

Temperature: 30° C.

Flow rate=0.75 ml/min

Mobile phase=0.01 M H₃PO₄, B═CH₃CN

Gradient: →0.5 min 90% A→4.5 min 10% A→6.5 min 10% A

Method 3 (HPLC):

Column: Kromasil C18 60*2, L-R

Temperature: 30° C.

Flow rate=0.75 ml/min

Mobile phase: A=0.005 M HClO₄, B═CH₃CN

Gradient: →0.5 min 98% A→4.5 min 10% A→6.5 min 10% A

Method 4 (HPLC):

Column: Symmetry C18 2.1×150 mm

Column oven: 50° C.

Flow rate=0.6 ml/min

Mobile phase: A=0.6 g 30% strength HCl/l water, B═CH₃CN

Gradient: 0.0 min 90% A→4.0 min 10% A→9 min 10% A

Method 5 (LC-MS):

MHZ-2Q, Instrument Micromass Quattro LCZ

Column Symmetry C18, 50 mm×2.1 mm, 3.5 μm

Temperature: 40° C.

Flow rate=0.5 ml/min

Mobile phase A=CH₃CN+0.1% formic acid, mobile phase B=water+0.1% formicacid

Gradient: 0.0 min 10% A→4 min 90% A→6 min 90% A

Method 6 (LC-MS):

MHZ-2P, Instrument Micromass Platform LCZ

Column Symmetry C18, 50 mm×2.1 mm, 3.5 μm

Temperature: 40° C.

Flow rate=0.5 ml/min

Mobile phase A=CH₃CN+0.1% formic acid, mobile phase B=water+0.1% formicacid

Gradient: 0.0 min 10% A→4 min 90% A→6 min 90% A

Method 7 (LC-MS):

MHZ-7Q, Instrument Micromass Quattro LCZ

Column Symmetry C18, 50 mm×2.1 mm, 3.5 μm

Temperature: 40° C.

Flow rate=0.5 ml/min

Mobile phase A=CH₃CN+0.1% formic acid, mobile phase B=water+0.1% formicacid

Gradient: 0.0 min 5% A→1 min 5% A→5 min 90% A→6 min 90% A

Method 8 (LC-MS):

Column: Symmetry C 18 2.1×150 mm

Column oven: 50° C.

Flow rate=0.9 ml/min

Mobile phase: A=0.3 g 30% strength HCl/l water, B═CH₃CN

Gradient: 0.0 min 90% A→3.0 min 10% A→6.0 min 10% A

Method 9 (HPLC):

Column: chiral stationary silica gel phase, based on the opticallyactive monomer

N-methacrylacyl-L-leucine-dicyclopropylmethylamide

Flow rate=15 ml/min

Mobile phase: isohexane/ethyl acetate 20:80

Method 10 (HPLC):

Column: Symmetry C18 2.1×150 mm

Column oven: 50° C.

Flow rate=0.9 ml/min

Mobile phase: A=CH₃CN, B=0.3 g 30% strength HCl/l water

Gradient: 0.0 min 10% A→3.0 min 90% A→6.0 min 90% A

Method 11 (HPLC):

Column: Symmetry C18 2.1×150 mm

Column oven: 70° C.

Flow rate=0.9 ml/min

Mobile phase: A=CH₃CN, B=0.3 g 30% strength HCl/l water

Gradient: 0.0 min 2% A→2.5 min 95% A→5.0 min 95% A

Method 12 (preparative HPLC):

Special method developed for removing the para-isomer:

Column: YMC silica gel ODS AQ, 11 μm; 250×30 mm

Flow rate=45 ml/min

Mobile phase: 0.2% strength trifluoroacetic acid/acetonitrile 85/15(v/v)

Detection: UV @ 220 nm

Sample application: 2.25 ml of a solution of 60 g of product dissolvedin 300 ml of

DMSO and 350 ml of 0.2% strength trifluoroacetic acid

Cycle time: 6.1 min

Method WTB (HPLC):

HP1100,

Column: LiChroCart 75-5 LiChrospher 100 RP-18 5 μm

Column oven: 40° C.

Flow rate=2.5 ml/min

Mobile phase: A=water with 0.05% TFA, B═CH₃CN with 0.05% TFA

Gradient: 0.0 min 90% A→0.05 min 90% A→5.0 min 5% A→7.0 min 5% A→7.05min 90% A→8.0 min 90% A

Preparative HPLC or RP-HPLC:

Reverse Phase

Column: GROM-SIL 120 ODS-4 HE 10 μm, 250*30 mm

Mobile phase: ACN/water gradient

1. A compound of the general formula (I)

in which A is attached via position 2, 3, 5 or 6 to the aromatic ringand A represents oxygen or NR⁶, E represents oxygen, CR⁹R¹⁰ or NR⁷, Yrepresents oxygen or NR⁸, D and X are identical or different andrepresent in each case oxygen or sulfur, G represents hydrogen, or Grepresents C₆-C₁₀-aryl, where C₆-C₁₀-aryl may optionally be substitutedby up to three substituents selected from the group consisting ofhalogen, hydroxyl, nitro, cyano, C₁-C₆-alkoxy, hydroxy-carbonyl,C₁-C₆-alkoxycarbonyl, amino, mono- or di-C₁-C₆-alkylamino, mono- ordi-C₁-C₆-alkylaminocarbonyl and C₁-C₆-alkyl, where C₁-C₆-alkoxy,C₁-C₆-alkoxycarbonyl, mono- or di-C₁-C₆-alkylamino, mono- ordi-C₁-C₆-alkylaminocarbonyl or C₁-C₆-alkyl may optionally be substitutedby up to three substituents selected from the group consisting ofhalogen, hydroxyl, C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,hydroxycarbonyl, C₁-C₆-alkoxycarbonyl, mono- ordi-C₁-C₆-alkylaminocarbonyl and C₆-C₁₀-aryl, or G representsC₆-C₁₀-aryl, where C₆-C₁₀-aryl may optionally be substituted by phenyl,where phenyl may optionally be substituted by up to three substituentsselected from the group consisting of halogen, hydroxyl, C₁-C₆-alkoxy,amino, mono- or di-C₁-C₆-alkylamino, hydroxycarbonyl,C₁-C₆-alkoxycarbonyl, mono- or di-C₁-C₆-alkylaminocarbonyl andC₁-C₆-alkyl, where C₁-C₆-alkyl for its part may optionally besubstituted by up to three substituents selected from the groupconsisting of hydroxyl, C₁-C₆-alkoxy, amino, mono- ordi-C₁-C₆-alkylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl and mono- ordi-C₁-C₆-alkylaminocarbonyl, or G represents C₆-C₁₀-aryl, whereC₆-C₁₀-aryl may optionally be substituted by phenyl, where phenyl mayoptionally be substituted by C₅-C₆-heteroaryl or C₅-C₇-heterocyclyl,where C₅-C₆-heteroaryl or C₅-C₇-heterocyclyl for their part mayoptionally be substituted by up to three substituents selected from thegroup consisting of halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, amino, mono- ordi-C₁-C₆-alkylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl and mono- ordi-C₁-C₆-alkylaminocarbonyl, or G represents C₆-C₁₀-aryl, whereC₆-C₁₀-aryl may optionally be substituted by a group of the followingformula

G represents C₅-C₁₀-heteroaryl or C₅-C₇-heterocyclyl, whereC₅-C₁₀-heteroaryl or C₅-C₇-heterocyclyl may optionally be substituted byup to three substituents selected from the group consisting of halogen,nitro, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy, amino, mono- ordi-C₁-C₆-alkylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl and mono ordi-C₁-C₆-alkylaminocarbonyl, or G represents C₃-C₁₀-cycloalkyl, whereC₃-C₁₀-cycloalkyl may optionally be substituted by up to threesubstituents selected from the group consisting of halogen, nitro,cyano, hydroxyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, amino, mono- ordi-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino, hydroxycarbonyl,C₁-C₆-alkoxycarbonyl and mono or di-C₁-C₆-alkylaminocarbonyl, R¹, R², R³and R⁴ are identical or different and each represent hydrogen, amino,mono- or di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino, C₆-C₁₀-aryl orC₁-C₆-alkyl, where C₁-C₆-alkyl may optionally be substituted by up tothree substituents selected from the group consisting of hydroxyl,C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,C₁-C₆-alkylcarbonylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl and monoor di-C₁-C₆-alkylaminocarbonyl, and where C₆-C₁₀-aryl may optionally besubstituted by up to three substituents selected from the groupconsisting of halogen, hydroxyl, C₁-C₆-alkoxy, amino, mono- ordi-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino, hydroxycarbonyl,C₁-C₆-alkoxycarbonyl, mono or di-C₁-C₆-alkylaminocarbonyl andC₁-C₆-alkyl, where C₁-C₆-alkyl may optionally be substituted by up tothree substituents selected from the group consisting of hydroxyl,C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,C₁-C₆-alkylcarbonylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl andmono- or di-C₁-C₆-alkylaminocarbonyl, or R¹ and R² or R³ and R⁴ togetherwith the carbon atom to which they are attached form a C₃-C₆-cycloalkylring, where the C₃-C₆-cycloalkyl ring may optionally be substituted byup to three substituents selected from the group consisting of halogen,hydroxyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, amino, mono- ordi-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino, hydroxycarbonyl,C₁-C₆-alkoxycarbonyl and mono- or di-C₁-C₆-alkylaminocarbonyl, or R¹ andR³ together with the carbon atoms to which they are attached form aC₃-C₆-cycloalkyl ring, where the C₃-C₆-cycloalkyl ring may optionally besubstituted by up to three substituents selected from the groupconsisting of halogen, hydroxyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, amino, mono-or di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino, hydroxycarbonyl,C₁-C₆-alkoxycarbonyl and mono- or di-C₁-C₆-alkylaminocarbonyl, R⁵represents hydrogen, halogen, hydroxyl, C₁-C₆-alkoxy, amino, mono- ordi-C₁-C₆-alkylamino or C₁-C₆-alkyl, where C₁-C₆-alkoxy, mono- ordi-C₁-C₆-alkylamino or C₁-C₆-alkyl may optionally be substituted by upto three substituents selected from the group consisting of hydroxyl,C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino, hydroxycarbonyl,C₁-C₆-alkoxycarbonyl and mono- or di-C₁-C₆-alkylaminocarbonyl, R⁶, R⁷and R⁸ are identical or different and represent in each case hydrogen orC₁-C₆-alkyl, where C₁-C₆-alkyl may optionally be substituted by up tothree substituents selected from the group consisting of hydroxyl,C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,C₁-C₆-alkylcarbonylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl andmono- or di-C₁-C₆-alkylaminocarbonyl, R⁹ and R¹⁰ are identical ordifferent and represent in each case hydrogen, NR¹¹R¹², OR¹³ orC₁-C₆-alkyl, where C₁-C₆-alkyl may optionally be substituted by up tothree substituents selected from the group consisting of hydroxyl,C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,C₁-C₆-alkylcarbonylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl andmono- or di-C₁-C₆-alkylaminocarbonyl, R¹¹, R¹² and R¹³ are identical ordifferent and represent in each case hydrogen or C₁-C₆-alkyl, whereC₁-C₆-alkyl may optionally be substituted by up to three substituentsselected from the group consisting of hydroxyl, C₁-C₆-alkoxy, amino,mono- or di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino, hydroxycarbonyl,C₁-C₆-alkoxycarbonyl and mono- or di-C₁-C₆-alkylaminocarbonyl, or atautomer, a stereioisomer, a stereoisomeric mixture or apharmacologically acceptable salt thereof.
 2. A compound of the generalformula (I) as claimed in claim 1, in which A is attached via position2, 3, 5 or 6 to the aromatic ring, and A represents oxygen or NR⁶, Erepresents oxygen, CR⁹R¹⁰ or NR⁷, Y represents oxygen or NR⁸, D and Xare identical or different and represent in each case oxygen or sulfur,G represents hydrogen, or G represents C₆-C₁₀-aryl, where C₆-C₁₀-arylmay optionally be substituted by up to three substituents independentlyof one another selected from the group consisting of halogen, hydroxyl,nitro, cyano, C₁-C₆-alkoxy, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl,amino, mono- or di-C₁-C₆-alkylamino, mono- ordi-C₁-C₆-alkylaminocarbonyl and C₁-C₆-alkyl, where C₁-C₆-alkoxy,C₁-C₆-alkoxycarbonyl, mono- or di-C₁-C₆-alkylamino, mono- ordi-C₁-C₆-alkylaminocarbonyl or C₁-C₆-alkyl may optionally be substitutedby up to three substituents independently of one another selected fromthe group consisting of halogen, hydroxyl, C₁-C₆-alkoxy, amino, mono- ordi-C₁-C₆-alkylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl, mono- ordi-C₁-C₆-alkylaminocarbonyl and C₆-C₁₀-aryl, or G representsC₆-C₁₀-aryl, where C₆-C₁₀-aryl may optionally be substituted by phenyl,where phenyl may optionally be substituted by up to three substituentsindependently of one another selected from the group consisting ofhalogen, hydroxyl, C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,hydroxycarbonyl, C₁-C₆-alkoxycarbonyl, mono- ordi-C₁-C₆-alkylaminocarbonyl and C₁-C₆-alkyl, where C₁-C₆-alkyl for itspart may optionally be substituted by up to three substituentsindependently of one another selected from the group consisting ofhydroxyl, C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,hydroxycarbonyl, C₁-C₆-alkoxycarbonyl and mono- ordi-C₁-C₆-alkylaminocarbonyl, or G represents C₆-C₁₀-aryl, whereC₆-C₁₀-aryl may optionally be substituted by phenyl, where phenyl mayoptionally be substituted by C₅-C₆-heteroaryl or C₅-C₇-heterocyclyl,where C₅-C₆-heteroaryl or C₅-C₇-heterocyclyl for their part mayoptionally be substituted by up to three substituents independently ofone another selected from the group consisting of halogen, C₁-C₆-alkyl,C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino, hydroxycarbonyl,C₁-C₆-alkoxycarbonyl and mono- or di-C₁-C₆-alkylaminocarbonyl, or Grepresents C₆-C₁₀-aryl, where C₆-C₁₀-aryl may optionally be substitutedby a group of the following formula

G represents C₅-C₁₀-heteroaryl or C₅-C₇-heterocyclyl, whereC₅-C₁₀-heteroaryl or C₅-C₇-heterocyclyl may optionally be substituted byup to three substituents independently of one another selected from thegroup consisting of halogen, nitro, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy,amino, mono- or di-C₁-C₆-alkylamino, hydroxycarbonyl,C₁-C₆-alkoxycarbonyl and mono- or di-C₁-C₆-alkylaminocarbonyl, or Grepresents C₃-C₁₀-cycloalkyl, where C₃-C₁₀-cycloalkyl may optionally besubstituted by up to three substituents independently of one anotherselected from the group consisting of halogen, nitro, cyano, hydroxyl,C₁-C₆-alkyl, C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,C₁-C₆-alkylcarbonylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl andmono- or di-C₁-C₆-alkylaminocarbonyl, R¹, R², R³ and R⁴ are identical ordifferent and represent in each case hydrogen, amino, mono- ordi-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino, C₆-C₁₀-aryl orC₁-C₆-alkyl, where C₁-C₆-alkyl may optionally be substituted by up tothree substituents independently of one another selected from the groupconsisting of hydroxyl, C₁-C₆-alkoxy, amino, mono- ordi-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino, hydroxycarbonyl,C₁-C₆-alkoxycarbonyl and mono- or di-C₁-C₆-alkylaminocarbonyl, and whereC₆-C₁₀-aryl may optionally be substituted by up to three substituentsselected from the group consisting of halogen, hydroxyl, C₁-C₆-alkoxy,amino, mono- or di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino,hydroxycarbonyl, C₁-C₆-alkoxycarbonyl, mono- ordi-C₁-C₆-alkylaminocarbonyl and C₁-C₆-alkyl, where C₁-C₆-alkyl mayoptionally be substituted by up to three substituents independently ofone another selected from the group consisting of hydroxyl,C₁-C₆-alkoxy, amino,-mono- or di-C₁-C₆-alkylamino,C₁-C₆-alkylcarbonylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl andmono- or di-C₁-C₆-alkylaminocarbonyl, where R¹, R², R³ and R⁴ are notsimultaneously hydrogen, or R¹ and R² or R³ and R⁴ together with thecarbon atom to which they are attached form a C₃-C₆-cycloalkyl ring,where the C₃-C₆-cycloalkyl ring may optionally be substituted by up tothree substituents independently of one another selected from the groupconsisting of halogen, hydroxyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, amino, mono-or di-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino, hydroxycarbonyl,C₁-C₆-alkoxycarbonyl and mono- or di-C₁-C₆-alkylaminocarbonyl, or R¹ andR³ together with the carbon atoms to which they are attached form aC₃-C₆-cycloalkyl ring, where the C₃-C₆-cycloalkyl ring may optionally besubstituted by up to three substituents independently of one anotherselected from the group consisting of halogen, hydroxyl, C₁-C₆-alkyl,C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,C₁-C₆-alkylcarbonylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl andmono- or di-C₁-C₆-alkylaminocarbonyl, R⁵ represents hydrogen, halogen,hydroxyl, C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino orC₁-C₆-alkyl, where C₁-C₆-alkoxy, mono- or di-C₁-C₆-alkylamino orC₁-C₆-alkyl may optionally be substituted by up to three substituentsindependently of one another selected from the group consisting ofhydroxyl, C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,hydroxycarbonyl, C₁-C₆-alkoxycarbonyl and mono- ordi-C₁-C₆-alkylaminocarbonyl, R⁶, R⁷ and R⁸ are identical or differentand represent in each case hydrogen or C₁-C₆-alkyl, where C₁-C₆-alkylmay optionally be substituted by up to three substituents independentlyof one another selected from the group consisting of hydroxyl,C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,C₁-C₆-alkylcarbonylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl andmono- or di-C₁-C₆-alkylaminocarbonyl, R⁹ and R¹⁰ are identical ordifferent and represent in each case hydrogen, NR¹¹R¹², OR¹³ orC₁-C₆-alkyl, where C₁-C₆-alkyl may optionally be substituted by up tothree substituents independently of one another selected from the groupconsisting of hydroxyl, C₁-C₆-alkoxy, amino, mono- ordi-C₁-C₆-alkylamino, C₁-C₆-alkylcarbonylamino, hydroxycarbonyl,C₁-C₆-alkoxycarbonyl and mono- or di-C₁-C₆-alkylaminocarbonyl, R¹¹, R¹²and R¹³ are identical or different and represent in each case hydrogenor C₁-C₆-alkyl, where C₁-C₆-alkyl may optionally be substituted by up tothree substituents selected from the group consisting of hydroxyl,C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,C₁-C₆-alkylcarbonylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl andmono- or di-C₁-C₆-alkylaminocarbonyl, or a tautomer, a stereoisomer, astereoisomeric mixture or a pharmacologically acceptable salt thereof.3. A compound of the general formula (I) as claimed in claim 1 or 2, inwhich A is attached via position 2, 3, 5 or 6 to the aromatic ring and Arepresents NR⁶, E represents NR⁷, Y represents NR⁸, D and X representoxygen, G represents C₆-C₁₀-aryl, where C₆-C₁₀-aryl may optionally besubstituted by up to three substituents independently of one anotherselected from the group consisting of halogen, hydroxyl, cyano andC₁-C₆-alkyl, where C₁-C₆-alkyl may optionally be substituted by up tothree substituents of halogen, or G represents C₅-C₆-heteroaryl, whereC₅-C₆-heteroaryl may optionally be substituted by up to threesubstituents independently of one another selected from the groupconsisting of halogen and C₁-C₃-alkyl, or G representsC₃-C₁₀-cycloalkyl, where C₃-C₁₀-cycloalkyl may optionally be substitutedby up to three substituents C₁-C₆-alkyl, R¹, R² and R³ are identical ordifferent and represent in each case hydrogen or represent C₁-C₃-alkyl,R⁴ represents hydrogen, C₆-C₁₀-aryl or C₁-C₆-alkyl, where C₁-C₆-alkylmay optionally be substituted by up to three substituents independentlyof one another selected from the group consisting of hydroxyl,C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,C₁-C₆-alkylcarbonylamino, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl andmono- or di-C₁-C₆-alkylaminocarbonyl, and where C₆-C₁₀-aryl mayoptionally be substituted by up to three substituents independently ofone another selected from the group consisting of halogen, hydroxyl,C₁-C₆-alkoxy and C₁-C₆-alkyl, where R¹, R², R³ and R⁴ do notsimultaneously represent hydrogen, R⁵ represents hydrogen, halogen,hydroxyl, amino, mono- or di-C₁-C₆-alkylamino or C₁-C₆-alkyl, whereC₁-C₆-alkyl may optionally be substituted by up to three substituentsindependently of one another selected from the group consisting ofhydroxyl, C₁-C₆-alkoxy, amino, mono- or di-C₁-C₆-alkylamino,hydroxycarbonyl, C₁-C₆-alkoxycarbonyl and mono- ordi-C₁-C₆-alkylaminocarbonyl, R⁶, R⁷ and R⁸ represent hydrogen, or atautomer, a stereoisomer, a stereoisomeric mixture or apharmacologically acceptable salt thereof.
 4. A compound of the generalformula (I) as claimed in claim 1, 2 or 3, where the radical A isattached via position 3 to the aromatic ring.
 5. A compound of thegeneral formula (I) as claimed in claim 1, 2 or 3, where D and X andrepresent oxygen.
 6. A compound of the general formula (I) as claimed inclaim 1, 2 or 3, where A, E and Y represent NH.
 7. A compound of thegeneral formula (I) as claimed in claim 1, 2 or 3, where G representssubstituted phenyl.
 8. A compound of the general formula (I) as claimedin claim 1, 2 or 3, where R¹, R² and R⁵ represent hydrogen and R³ and R⁴represent methyl.
 9. A process for preparing the compounds of theformula (I) as claimed in claim 1, which comprises [A] reactingcompounds of the general formula (II)

in which A is attached via position 2, 3, 5 or 6 to the aromatic ringand R¹, R², R³, R⁴, R⁵, A, X and Y are as defined above, with compoundsof the general formula (III)D=C═N-G   (III) in which D and G are as defined above to give compoundsof the general formula (Ia)

in which A is attached via position 2, 3, 5 or 6 to the aromatic ringand R¹, R², R³, R⁴, R⁵, A, D, G, X and Y are as defined above, or [B]reacting compounds of the general formula (II) with compounds of thegeneral formula (IV)

in which D, E and G are as defined above and L¹ represents p-nitrophenylor halogen, preferably bromine or chlorine, to give compounds of thegeneral formula (I)

in which A is attached via position 2, 3, 5 or 6 to the aromatic ringand R¹, R², R³, R⁴, R⁵, A, D, E, G, X and Y are as defined above, or [C]reacting compounds of the general formula (V)

in which —NCD is attached via position 2, 3, 5 or 6 to the aromatic ringand R¹, R², R³, R⁴, R⁵, D, X and Y are as defined above with compoundsof the general formula (VI)H-M-G   (VI) in which G is as defined above and M represents oxygen orNR⁷, where R⁷ is as defined above, to give compounds of the generalformula (Ib)

in which —NH—C(D)-M-G is attached via position 2, 3, 5 or 6 to thearomatic ring and R¹, R², R³, R⁴, R⁵, D, G, M, X and Y are as definedabove.
 10. A compound of the general formula (I) as claimed in claim 1,2 or 3 for controlling disorders.
 11. A medicament, comprising compoundsof the general formula (I) as claimed in claim 1, 2 or 3 in combinationwith at least one pharmaceutically acceptable, pharmaceutically safecarrier or excipient.
 12. The use of compounds of the general formula(I) as claimed in claim 1, 2 or 3 for preparing as medicament fortreating viral disorders.
 13. A medicament as claimed in claim 12, fortreating viral disorders.
 14. A method for controlling viral disordersin humans and animals by administration of an antivirally effectiveamount of at least one compound as claimed in any of claims 1 to 3.